KR101544498B1 - Compositions for the treatment of neoplastic diseases - Google Patents

Abstract

A pharmaceutical composition and method for the treatment of a tumorous disease and comprising a taxane such as docetaxel comprising a CYP3A4 inhibitor such as ritonavir. Also included are methods of treating tumoral diseases in which administration of Taxane and / or CYP3A4 administration is introduced simultaneously or separately. Further, a kit for performing the above method is included. Also included is a solid pharmaceutical tex- ton composition for oral administration comprising a substantially amorphous taxane, a carrier and a surfactant.

Description

≪ Desc / Clms Page number 1 > COMPOSITIONS FOR THE TREATMENT OF NEOPLASTIC DISEASES &

The present invention relates to pharmaceutical compositions. Specifically, although not exclusively, it relates to compositions and methods for the treatment of tumorous diseases.

Administration of the drug in the oral form offers several advantages. The availability of oral anticancer agents is particularly important when the treatment is to be applied chronically, for example, when a 5-fluorouracil (5-FU) prodrug (e.g., capecitabine) 1] is effective to optimize the effectiveness of drugs. In addition, oral medications can be administered on an outpatient basis or at home and can reduce costs by increasing convenience and patient quality of life and reducing hospital outbreaks [2]. Therefore, it is advantageous to attempt to administer an anticancer agent orally.

The invention will now be described by way of example only with reference to the accompanying drawings.
FIG. 1 is a graph showing the blood concentration of docetaxel versus time. FIG. 1 is a graph showing the blood concentration of docetaxel versus time, with or without administration of ritonavir (RTV) (when ritonavir was given 60 min before and simultaneously with docetaxel) Without); Oral docetaxel Dose: 100 mg. Commercially available intravenously administered docetaxel formulation (takso terephthalate ^{® (Taxotere ®): 2ml =} 80mg docetaxel; additives polysorbate 80) ethanol 95%: water (13: 87) is diluted with drinking the patient with the 100ml water 10 mg / ml docetaxel solution (10 ml of 10 mg / ml solution). Ritonavir dose: 1 capsule containing 100mg of ritonavir eoga (Nord builder ^® (Norvir ^®)).
Figure 2 is a ritonavir graph is empty, showing the blood concentration versus time, empty ritonavir before 60 minutes orally administered docetaxel and the same time of or oral docetaxel (dose 100mg; Nord builder ^® (Norvir ^®), capsules) compared to oral administration do. T = 0 is when docetaxel is administered. Therefore, the first part of the curve corresponding to the ritonavir administered prior to docetaxel administration is not shown. Oral docetaxel Dose: 100 mg. Commercially available intravenously administered docetaxel formulation (takso terephthalate ^{® (Taxotere ®): 2ml =} 80mg docetaxel; additives polysorbate 80) ethanol 95%: water (13: 87) is diluted with drinking the patient with the 100ml water 10 mg / ml docetaxel solution (10 ml of 10 mg / ml solution). Ritonavir dose: 1 capsule containing 100mg of ritonavir eoga (Nord builder ^® (Norvir ^®)).
Figure 3 is a pharmacokinetic model of oral docetaxel combined with ritonavir (RTV). Other parts of the pharmacokinetic model are as follows:
C1 - Gastrointestinal track (ingestion of oral docetaxel)
C2-central part (docetaxel)
C3-first peripheral portion (docetaxel)
C4-second peripheral portion (docetaxel)
C5-Gastrointestinal track (LitonaVia injection part)
C6 - central part (ritonavir)
C7-active CYP3A4 enzyme
C8-inactive CYP3A4 enzyme;
4 is a graph depicting a number of subjects, wherein each line is an object and represents the relative amount of active CYP3A4 enzyme over time in oral docetaxel combined with ritonavir;
Figure 5 shows the dissolution test results of paclitaxel solid dispersion versus paclitaxel physical mixture (conditions: 900 mL WfI, 37 DEG C, 75 rpm);
Figure 6 shows the dissolution test results of paclitaxel (PCT) solid dispersion capsules with and without sodium dodecylsulfate (condition: 900 mL WfI, 37 DEG C, 75 rpm);
Figure 7 shows the dissolution test results of paclitaxel solid dispersion when sodium dodecylsulfate was introduced into the solid dispersion or added to the capsules (conditions: 500 mL WfI, 37 DEG C, 75 rpm (SDS added to the capsule at 100 rpm) );
Figure 8 shows dissolution test results of various carriers and paclitaxel solid dispersion (conditions: 500 mL WfI, 37 DEG C, 100 rpm);
Figure 9 shows the dissolution test results of various carriers and paclitaxel / PVP-K17 solid dispersions (conditions: 25 mL WfI, 37 DEG C, 7200 rpm);
Figure 10 shows dissolution test results of paclitaxel solid dispersion in various media (conditions: 500 mL FaSSIF (light gray), 37 C, 75 rpm; or 500 mL SGF _sp and 629 mL SIF _sp , 37 C, 75 rpm (charcoal));
Figure 11 shows the solubility of docetaxel in five different formulations (see Table 16). A: anhydrous docetaxel; B: amorphous docetaxel; C: Physical mixture of anhydrous docetaxel, PVP-K-30 and SDS; D: a physical mixture of amorphous docetaxel, PVP-K30 and SDS; E: Solid dispersion of amorphous docetaxel, PVP-K30 and SDS (dissolution conditions: ± 6 mg docetaxel, 25 mL WfI, 37 ° C., 720 rpm);
Figure 12 shows the solubility of docetaxel in solid dispersion with different carriers (see Table 16). E: solid dispersion of amorphous docetaxel, PVP-K30 and SDS; F: Solid dispersion of amorphous docetaxel, HPβ-CD and SDS (dissolution conditions: ± 6 mg docetaxel, 25 mL WfI, 37 ° C., 720 rpm);
Figure 13 shows the solubility of docetaxel in the solid dispersion of PVP with various chain lengths (see Table 16). E: solid dispersion of amorphous docetaxel, PVP-K30 and SDS; G: Solid dispersion of amorphous docetaxel, PVP-K12 and SDS; H: solid dispersion of amorphous docetaxel, PVP-K17 and SDS; I: solid dispersion of amorphous docetaxel, PVP-K25 and SDS; J: solid dispersion of amorphous docetaxel, PVP-K90 and SDS (dissolution conditions: ± 6 mg docetaxel, 25 mL WfI, 37 ° C., 720 rpm);
Figure 14 shows the solubility of docetaxel in solid dispersion with various drug loads (see Table 16). E: 1/11 docetaxel; K: 5/7 docetaxel; L: 1/3 docetaxel; M: 1/6 docetaxel; N: 1/21 docetaxel (dissolution conditions: ± 6 mg docetaxel, 25 mL WfI, 37 ° C., 720 rpm);
Figure 15 shows dissolution results relating to the relative amounts of docetaxel, PVP-K30 and SDP dissolved in solid dispersion in comparison to literature data of solid dispersion of docetaxel and PVP K30 [Chen et al., 95];
Figure 16 shows dissolution results relating to the absolute amount of dissolved docetaxel in solid dispersion of docetaxel, PVP-K30 and SDS compared to literature data of solid dispersion of docetaxel and PVP K30 [Chen et al., 95];
Figure 17 shows the dissolution test results of docetaxel capsules (15 mg docetaxel and PVP-K30 + SDS per capsule) compared to literature data [Chen et al., 95].
Figure 18 shows dissolution results relating to the absolute amount of dissolved docetaxel in solid dispersion of docetaxel, PVP-K30 and SDS. The dissolution test was performed in a simulated intestinal fluid sine pancreatin (SIF _sp );
Figure 19 shows dissolution results with respect to the relative amounts of docetaxel, PVP-K30 and dissolved docetaxel in solid dispersion of SDS. The dissolution test was performed in a simulated intestinal fluid sine pancreatin (SIF _sp );
Figure 20 shows the pharmacokinetic curves of patients who received docetaxel and ritonavir simultaneously in the first cycle. In the second cycle, the patient received docetaxel and ritonavir simultaneously at t = 0 and then received an additional dose of ritonavir at t = 4h;
Figure 21 shows the pharmacokinetic curves for four patients who received a liquid formulation of docetaxel and / or solid dispersion (referred to as MODRA) comprising docetaxel;
Figure 22 shows the pharmacokinetic curve for patients receiving liquid oral formulations of docetaxel versus patients receiving solid oral formulations (MODRA) of docetaxel;
Figure 23 shows pharmacokinetic curves after intravenous and oral administration of docetaxel. Both intravenous and oral docetaxel were combined with ritonavir administration. NB The calculated bioavailability is corrected to the administered dose.

In general, oral administration of the drug is convenient and practical. However, the majority of anticancer drugs unfortunately have low and variable oral bioavailability [1]. Typical examples are widely used tex- ton, docetaxel, and paclitaxel, which have oral bioavailability of less than 10% [3,4]. Other anticancer agents with some higher bioavailability show higher variability. Topoisomerase I inhibitors, vinca alkaloids and mitoxantrone [1,5,6]. In view of the narrow therapeutic window, the variable bioavailability can lead to a reduced effect if unexpected toxic or therapeutic plasma levels are not achieved. Hellriegel et al. [7] have shown that plasma levels after oral administration are generally more variable after intravenous administration. Adequate oral bioavailability is important when drug exposure is a major determinant of chemotherapy [8]. Proper oral bioavailability is also important to prevent high local drug concentrations in the gastro-intestinal tract, which can lead to local toxicity.

Chen et al. [95] conducted an experiment to improve the solubility of the anti-cancer drug docetaxel in order to improve the bioavailability of the drug. Chen et al. Attempted to use solid dispersions of various carriers, namely glyceryl monostearate, PVP-K30 or Poloxamer 188 and docetaxel. Chen et al. Reported that the solubility of docetaxel increased by about 3.3 μg / mL after 20 minutes of Poloxamer 188 (in a standard dissolution test) and about 5.5 minutes after about 120 minutes when the ratio of docetaxel to poloxamer was 5:95 RTI ID = 0.0 > g / ml. ≪ / RTI > PVP-K30 increased the solubility of docetaxel to about 0.8 μg / mL after only 20 minutes and increased to a maximum of about 4.2 μg / mL after about 300 minutes. Glycerol monostearate scarcely increased the solubility of docetaxel at all. Therefore, the solubility and dissolution rate of docetaxel did not increase to particularly high values.

Higher affinity for drug carriers in the gastrointestinal track that limits absorption and variable and / or low oral bioavailability of anticancer drugs such as high efficacy of the drug due to extensive metabolism in the intestine and / or liver (first-pass effect) There are several important mechanisms that can explain [1,4,9]. Other important factors include structural instability and limited solubility of the drug in the gastrointestinal fluid, drug-drug and drug-food interactions, motility disorders, obstructive disorders, persistence of nausea and vomiting, or local toxicity in the gastrointestinal track .

In relation to drug carriers and metabolic enzymes that affect the bioavailability of oral drugs, the major drug carriers and metabolic enzymes responsible for low / variable oral bioavailability of anticancer drugs are P-glycoprotein (P-gp ) And cytochrome P450 (CYP) isoemzyme.

P-glycoprotein (P-gp) is an efflux pump that reduces the intracellular accumulation of a drug by releasing xenobiotic in the cell, or a membrane-coupled multidrug that functions by energy-dependent transport Lt; / RTI > P-gp has been implicated in the pathogenesis of hepatocellular capillary membranes, the blood-brain barrier and the luminal membrane of the intimal cells of the blood testis gland, the apical membrane of the syncytial trophoblast, the epithelial apical membrane membrane, and proximal tubules (exocrine tubules). P-gp may have important barrier functions in protective tissues against xenotoxin [9-12].

P-gp inhibits certain pharmaceutical compounds from crossing the mucosal cells of the small intestine, thus preventing systemic circulation. A wide range of drugs with diverse physico-chemical properties and pharmacological activities such as verapamil, quinidine and cyclosporin A (CsA) and novel active inhibitors GF120918 (elacridar), LY335979 (zosuquidar) and R101933, gp [13-18]. The mechanism by P-gp mediators influences the pharmacokinetics of anticancer drugs after intravenous administration competing with cytochrome P450 (CYP) -mediated intestinal or hepatic metabolism, P-gp-mediated bile emission, intestinal transport and renal elimination inhibition Can be given [19,20]. Only a few prospective randomized trials with combinations of anticancer drugs with or without Adjuvants were performed. These studies have shown that dose reduction of anticancer drugs is necessary to prevent some drug-related toxicity when combined with an adjuvant. Furthermore, these studies did not show any survival benefit with the combination of modulators and anticancer drugs [21-23].

For many anticancer drugs, cytochrome P450 (CYP) is the major oxidative drug metabolizing enzyme system. The CYP isoenzymes are highly expressed in the liver and liver, but the contribution of each isoenzymes to the metabolism of the drug is unknown. Intestinal excretion by this enzyme system plays an important role in limiting oral bioavailability of drugs [31]. Humans are excellent drug metabolizing enzymes and have four identified functional CYP3A4 enzymes, accounting for approximately 30% of liver CYP and over 70% of intestinal CYP expression [24,30,32,33].

Several P-gp modulators also appear to be substrates for CYP3A, the isoenzymes of the CYP system. Overlap in the substrate selectivity of P-gp and CYP3A in combination with their tissue localization suggests that the two proteins cooperate and constitute an absorption barrier against the toxic genoviotics [24-26]. Cummins et al. Confirmed this and demonstrated that P-gp can affect intestinal metabolism by modulating drug access to the intracellular metabolic enzyme system, particularly the isoenzyme CYP3A4 [27]. Thus, CYP3A and P-gp can play a role in limited and / or variable oral bioavailability of substrate drugs shared in the intestine.

Taxanes, park ratsacen and docetaxel have proven anti-cancer effects in several tumor types (eg, breast, ovary, head & neck, and non-small cell lung cancer [NSCLC]). Recently, the drug was administered intravenously in different dosages and schedules [34]. However, in oral formulations, the Takken has very low bioavailability. This is presumably due to the action of P-gp and CYP3A. Studies that attempted to increase the bioavailability of orally administered drugs have been performed in rats and humans using several anticancer drugs (eg, Taksen).

When paclitaxel is administered orally, the bioavailability is very low (< 10%). This is caused by the high affinity of paclitaxel for P-gp, which is present in the gastrointestinal track [4, 10, 35, 36]. In addition, presystemic elimination in the barrier and liver by CYP isoenzymes 3A4 and 2C8 can also play a role in the low oral bioavailability of paclitaxel [37-39]. Recent studies in wild-type and mdr1a P-gp knockout mice have unambiguously shown that P-gp limits the absorption of paclitaxel. In proof-of-concept studies of knockout mice compared to wild-type mice, investigators found that the area under the blood concentration-time curve (AUC) of paclitaxel after oral and intravenous administration was 6 Fold and 2-fold increase, respectively [4]. The fraction of unchanged paclitaxel found in the feces of wild-type mice after oral administration was 87% of the dose compared to 3% of the mdr1a P-gp knockout mice. Despite complete absorption in the gastrointestinal track, bioavailability does not increase by 100%, presumably due to first-pass / liver excretion [4, 40].

Based on this observation, several new studies have been initiated for P-gp inhibitors in combination with paclitaxel to enhance oral bioavailability. Studies in mice have shown that co-administration of SDZ PSC833, cyclosporine D analogue and a strong P-gp inhibitor with paclitaxel causes a 10-fold increase in systemic exposure [41]. Similar studies of CsA and paclitaxel with similar effects have been performed [42]. Oral bioavailability of wild-type rats increased from 9% to 67% when administered with CsA. It has also been noted that the plasma levels obtained in wild-type mice treated with CsA are much higher than those obtained in knockout mice treated with oral paclitaxel without CsA. This can be explained by increased uptake by P-gp inhibition in the gastrointestinal track and decreased elimination by CYP3A4 inhibition [42-45]. However, blocking of other yet unidentified drug carriers or drug clearance routes may be excluded.

Long-term oral administration of CsA is associated with an immunosuppressive effect that is unhealthy for the subject. Thus, an selective, non-immunosuppressive P-gp blocker, GF120918, has been explored to enhance oral bioavailability of paclitaxel, GF120918, in order to reverse the resistance of P-gp- mediated multi- Mainly developed [16]. In a recent published study, Bardelmeijer et al. Showed that GF120918 significantly increased oral bioavailability of paclitaxel [46]. The oral bioavailability of paclitaxel increased from 8.5% to 40% in wild-type rats and the paclitaxel pharmacokinetics in wild-type mice receiving GF120918 were similar to those found in the mdr1a / bP-gp knockout mice. Therefore, GF120918 is likely to effectively block P-gp in the intestines and not interfere with other pathways involved in paclitaxel uptake or elimination. Importantly, GF120918 has also recently been shown to be an effective inhibitor of the ABC drug transporter BCRP (ABCG2) [28,29].

Docetaxel is also a substrate for P-gp that was first shown in 1994 by Wils et al. [47,48]. Because of the promising results obtained with paclitaxel in combination with P-gp inhibitors, studies on mice were performed with docetaxel. These studies confirmed that P-gp also plays an important role in low bioavailability of docetaxel. AUC of oral docetaxel was increased 9-fold by co-administration with CsA [49]. In addition, administration with a CYP3A4 inhibitor, ritonavir, with an additional P-gp inhibitory property, was tested in rats. CYP3A4 is a major enzyme responsible for the metabolism of docetaxel in humans [50]. The inventors conducted preclinical studies on rats dosed with docetaxel and ritonavir and showed an apparent bioavailability increase of 4% to 183%. Extensive first-pass metabolism could also contribute significantly to lower bioavailability of oral docetaxel in rats [49]. The cytochrome P450 enzyme in the rat's intestine (referred to as Cyp) is different from that found in humans and has a different substrate specificity. In addition, the regulation of CYPs expression between mice and humans varies considerably due to differences in activity, expression and transcription factor regulation, such as the PXR of human CYP3A [88-92]. Therefore, in rats, this study may not be trusted to give any connotation to human outcomes because mouse physiology, enzymes, etc. are completely different from humans. Therefore, rat data can not be simply deduced to humans. Furthermore, studies on rats using extremely high doses of docetaxel (10-30 mg / kg) would be fatal to humans, as are high doses of ritonavir (12.5 mg / kg). For a person of 72 kg, this would mean 720-2160 mg of docetaxel. However, patients are currently being treated in hospital with doses of 100 to 200 mg docetaxel (intravenous). Obviously, this approach is not possible for humans because of the high degree of drug administered. Moreover, the rat data do not provide any evidence for the safety of oral access with this combination in humans

Based on the widespread preclinical results of mice, several clinical concept-based studies have begun. Patients with solid tumors received either a single course of 60 mg / m ² oral paclitaxel or 60 mg / m ² oral paclitaxel in combination with 15 mg / kg CsA as a single agent. Concomitant administration of oral CsA resulted in an 8-fold increase in systemic exposure to oral paclitaxel. In this study, the apparent bioavailability of oral paclitaxel increased from 4% in the absence of CsA to 47% in the presence of CsA [3]. This increase in systemic exposure seems to be caused most by inhibition of P-gp in the gastrointestinal track, but inhibition of paclitaxel metabolism could also contribute to this effect, as was concluded in preclinical studies [41,42]. In order to further increase systemic exposure of paclitaxel, a step-wise expansion study of oral paclitaxel capacity in combination with CsA found that the maximum tolerated dose was 300 mg / m ² and at higher doses the increase in AUC was dose-proportional [52]. At this highest dose level, a mass balance study was conducted to measure fecal excretion. At the highest dose level of 300 g / m ² , total fecal excretion was 76% and the parent drug 61%, which is explained by the incomplete absorption of paclitaxel orally administered in the gastrointestinal track Can be [53]. It was speculated that a large amount of the common Cremophor EL in the paclitaxel intravenous formulation used for oral administration inhibited the complete absorption of orally administered paclitaxel. Furthermore, the non-linear pharmacokinetics of intravenous paclitaxel and Cremophor EL, which is responsible for some irritable responses, were not absorbed after oral administration of paclitaxel from the undetected plasma concentration of Cremophor EL [54-56 ]. This may be an additional advantage of oral paclitaxel administration [51,52]. Next, to increase the duration of oral paclitaxel system exposure above the 0.1 μM threshold level, two doses of oral paclitaxel combined with CsA per day were explored in patients. At dose levels of 2 x 90 mg / m ² , systemic exposures of appropriately long paclitaxel above the 0.1 μM level were reached with an excellent safety profile [57]. In these studies, the patients were orally administered parenteral paclitaxel formulations (including cremophor EL and ethanol) [57]. Additionally, a dose-finding study of oral paclitaxel containing CsA showed that P-gp inhibition by CsA was maximal at a single dose of 10 mg / kg.

In another phase I study, patients received 1,000 mg GF120918 1 hour before oral paclitaxel [59]. The increase in systemic exposure to paclitaxel was the same as when combined with CsA. Based on these Phase I studies, Phase II studies have begun to investigate whether repeated oral administration of paclitaxel is feasible and active. Oral paclitaxel was given twice a day once a week in several tumor types: first- and second-line treatment of NSCLC [60], first-line treatment in advanced gastric cancer [99], and second in advanced breast cancer - line therapy [100]. All patients were treated twice a day with oral paclitaxel at a dose of 90 mg / m ² . CsA at a dose of 10 mg / kg was given 30 minutes before the administration of meprakitaxel. For advanced NSCLC patients, the overall response rate (ORR) was 26% of 23 evaluable patients [60]. This is similar to earlier studies in which the median time to progression was 3.5 months and the median overall survival was 6 months. These studies using several single agents, such as vinorelbine, gemcitabine and taxacene, showed a response rate of between 8% and 40% and the median overall survival ranged from 6-11 months [61-66 ].

In advanced gastric cancer, chemotherapy is given for a temporary purpose. Combination chemotherapy with agents such as 5-FU / doxorubicin or epirubicin / cisplatin / 5-FU in combination with mitomycin or methotrexate is a frequently used schedule and has a response rate between 20% and 50% [67-70]. Paclitaxel also exhibits anti-tumor activity in the first- and second-line treatment of advanced gastric cancer patients (ORR: 5% -23%) [71-73]. In this study, ORR was 32% of 24 evaluable patients. The toxicity profiles of the two weekly schedules of this day are well managed [99]. The most prevalent toxicity in the NSCLC patient group was grade 3/4 neutropenia, which was observed in 54% of patients. This is similar to the standard weekly-3-week intravenous paclitaxel schedule [65,66].

The predominance of neurotoxin was lower than that of the MeV-3 schedule, which can be explained by the lower peak plasma concentration of paclitaxel in this study. Although it may be questionable whether or not the concentration of paclitaxel plasma (in the presence of Cremophor EL) after intravenous administration can be compared to that after oral paclitaxel (in the absence of Cremophor EL) Were observed in patients receiving paclitaxel for 24 hours versus patients infused for 3 hours [74].

In docetaxel, a similar clinical concept-proof study was performed on patients with solid tumors. Patients received one course of oral docetaxel 75 mg / m ^{2 with} or without a single oral dose of CsA 15 mg / kg. Pharmacokinetic results showed that administration of oral CsA together resulted in a 7.3-fold increase in systemic exposure of docetaxel. The apparent bioavailability of oral docetaxel increased from 8% without CsA to 90% with CsA [75]. This increase in systemic exposure can be explained not only by CYP3A4 inhibition but also by P-gp in the gastrointestinal track by CsA, but the importance of both mechanisms can not be determined precisely. The effect of CsA on the bioavailability of docetaxel was less pronounced in rats [49] than in humans [75], but the reason for this moderate effect on mice is unclear. Phase II trials of weekly oral docetaxel plus advanced CsA for advanced breast cancer were also performed. The schedule was given weekly for 6 weeks and then rested for 2 weeks. A weekly oral dose of 100 mg docetaxel was given and led to an AUC equivalent to a weekly intravenous dose of 40 mg / m ² , which was fairly well tolerated [76]. CsA was given 30 minutes before dosing with oral docetaxel at a dose of 15 mg / kg. An intravenous dosage form of docetaxel was used as a dragging solution. Of the 25 patients who were able to assess the response, 52% of ORRs were noted.

The most frequently reported toxicities were neutropenia, diarrhea, hand toxicity and fatigue. However, hematologic toxicity appears to be less severe after intravenous administration [77]. In this study, the reaction rate is in the upper range of the results described in the literature [76-79].

In the AUC of docetaxel after oral administration, the patient's intra- and peripheral variability is in the same range as observed after intravenous administration of docetaxel (29-53%) [80,81].

Administration of CsA oral doses weekly or twice a day in combination with oral docetaxel or paclitaxel could lead to infection due to renal toxicity or immunosuppression [82]. Therefore, an alternative drug for improving the clinical bioavailability of oral docetaxel or paclitaxel would be desirable from the point of view of the present inventors.

The powerful weekly oral schedule by Taksen shows clinically meaningful activity in feasible and advanced breast, stomach and NSCLC. The oral schedule has a convenient and favorable hematological toxicity profile and the non-hematologic toxicity is acceptable.

This prior art appears to focus primarily on inhibiting the activity of P-gp to improve the bioavailability and pharmacokinetic properties of anticancer drugs. This was done using a variety of drugs, such as CsA and GF120918. Indicating that P-gp was shown to be the most important protein to block the bioavailability of the oral drug.

Thus, in one aspect, the invention provides a pharmaceutical composition for oral administration comprising a CYP3A4 inhibitor, such as taxane and rionavir, together with one or more pharmaceutically acceptable excipients.

The advantage of using ritonavir in combination with Taksen is that the oral bioavailability of the Takkasin is increased and more drug is absorbed from the intestine into the bloodstream. This is due to CYP3A4 inhibition and ancillary P-gp inhibiting properties which prevent the drug from being metabolized. The ritonavir also reduces the elimination of the taxane in the body by inhibition of CYP3A4 metabolism in the liver. This means that the higher blood concentration of the Takken is reached for a longer time. For example, the docetaxel metabolite is less pharmacologically active than docetaxel itself. Therefore, by metabolism inhibition of docetaxel, the most pharmacologically active forms are present in higher concentrations, and longer in the bloodstream. This provides a greater therapeutic effect. As a result, it may become possible to reduce the amount of taxane per dose. Inhibition of CYP3A4 also reduces interpatient variability in bioavailability and elimination due to different degrees of CYP activity in different patients.

Targeting or inhibiting CYP3A4 by ritonavir than by targeting P-gp improves oral bioavailability by inhibiting their metabolism. This, in turn, follows the prior art with a different approach.

The pharmaceutical compositions of the present invention may be formulated with any pharmaceutically acceptable carrier, adjuvant or vehicle together with any tacken, or pharmaceutically acceptable salt thereof, esters and ritonavir (or pharmaceutically acceptable salts thereof) Possible salts and esters). Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, Such as water, salts or protamine sulphates, disodium hydrogen phosphate, potassium hydrogen phosphate, sorbitan monooleate, sorbitan monooleate, sorbitan monooleate, sorbitan monooleate, sorbitan monooleate, glycerin, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, Based materials, polyethylene glycols, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers (such as sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose- , Polyethylene glycol, and wool fat. One, but not limited thereto. The pharmaceutical compositions of the present invention may include any conventional non-toxic pharmaceutically acceptable carrier, adjuvant or vehicle.

The pharmaceutical compositions of the present invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, powders or coated granules. Suspensions, solutions and emulsions, preferably those in aqueous vehicles, may also be introduced. Tablets may be formulated as immediate release, extended release, repeated release or sustained release. They may also, or alternatively, be effervescent, bilayer and / or coated tablets. The sustained release, repeated release and delayed release formulations may be for one or two active ingredients. The tablets may be formed from solid dispersions or solid solutions of taxanes and / or ritonavir. Capsules may be formulated to be immediate, sustained, repeated release or delayed release. These may be solid-filled or liquid-filled capsules. The sustained release, repeated release, delayed release formulation may be for one or two active ingredients. The capsules may be formed from solid dispersions or solid solutions of tacken and / or ritonavir, or the tacken and / or ritonavir may be dissolved or dispersed in the liquid. For example, a possible solvent for liquid filled capsules is triacetin. This appears to be a particularly good solvent for Park Ritak cells. The aqueous solution may be "ready for use" and may be prepared from powders or powders, and may be prepared from solid dispersion or dispersions or by solution mixing of taxanes and ritonavir. The aqueous solution may also contain polysorbate 80 and other pharmaceutical additives such as ethanol. In the case of oral tablets and capsules, commonly used carriers are sucrose, cyclodextrin, polyethylene glycol, polymethacrylate, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearate, mannitol, inulin, sugar (dextrose, Sucrose, fructose or lactose), HPMC (hydroxypropylmethylcellulose), PVP (polyvinylpyrrolidone), and corn starch. Lubricants such as magnesium stearate are also typically added. Useful diluents in capsule form for oral administration include lactose and dried corn starch. Other pharmaceutical additives that may be added for tablets and capsules are binders, fillers, fillers / binders, adsorbents, wetting agents, disintegrants, lubricants, glidants, surfactants, and the like. Tablets and capsules may be coated to change the appearance or properties of tablets and capsules, for example, to change the taste of tablets or capsules, or to coat a coating color. When the aqueous suspension is administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, any sweetener and / or flavoring and / or coloring matter may be added.

Solid dispersions or solid solutions of taxane and ritonavir may be formed using any suitable method and may include a carrier, such as a polymer. Such methods are well known to those skilled in the art [93,94]. In solid dispersion, taksen and ritonavir can be amorphous, crystalline or partially amorphous / partially crystalline. Often, organic solvents are used in the preparation of solid dispersions. This may be done by adding any suitable organic daily water such as TBA (tertiary butyl alcohol), ethanol, methanol, DMSO (dimethyl sulfoxide) and IPA (iso-propyl alcohol) have. Any method of removing organic and / or aqueous solvents in a solid dispersion solution can be used, for example, by freeze drying, spray drying, spray-freeze drying and vacuum drying.

In oral compositions, particularly solid compositions, taxanes and ritonavir may be present in the same dosage form or in separate dosage forms. When present in the same dosage form, taxanes and ritonavir can be formulated together, or they can be in separate fractions of a multi-dose dosage form, such as multi-layered tablets or fractionated capsules.

For compositions comprising a modified release formulation, such as slow release, repeated release and delayed release formulations, the object is to provide a composition comprising one or two active ingredients for a prolonged period of time after administration, will be.

Repeated emissive formulations, such as tablets or capsules, may release the appropriate amount of a taxane (e.g., docetaxel) and ritonavir immediately (e.g., at time t = 0 hour) and the addition of ritonavir (E. G., Time t = 4 hours, typically when reaching the highest concentration of C _max in the blood of ritonavir). &Lt; / RTI &gt; This may be achieved, for example, by separating an initial dose of docetaxel and ritonavir from an additional dose of ritonavir by an enteric coating or polymeric coating comprising an enzymatically degradable linkage that allows for a coating that is degraded and dissolved in the intestine . Alternatively, this can be accomplished by coating the coated granules with only the ritonavir and the uncoated granules with docetaxel and ritonavir, and filling the capsules with the coated granules and the uncoated granules. This could, of course, also be accomplished by combining repeated release ritonavir tablets / capsules with immediate release docetaxel tablets / capsules. Any suitable enteric coating may be used, for example, suitable acrylic derivatives, such as cellulose acetate phthalate, polyvinylacetate phthalate and polymethacrylate.

In one embodiment, a second ritonavir supplement (and thus three of the total dosages) is administered on the same principle, i. E. After several hours after the first additional dose (e. G. Gt; _{Cmax &lt; / RTI} &gt; was reached).

A delayed emissive formulation allows, for example, the release of the retentate amount of ritonavir slowly after releasing an appropriate amount of the taxane and an initial amount of priming / loading of the ritonavir. For example, this could be done by a single oral dosage form of docetaxel and ritonavir, or a combination of docetaxel in immediate release tablets / capsules and renotavir in delayed release tablets / capsules.

Modified emissive formulations may employ, for example, inert insolubles, hydrophilic materials, ion-exchange resins, osmo-controlled formulations and storage systems. A typical modified release system could, for example, consist of the following materials: active drug (s), release modifier (s) (e.g., matrix formers, film formers), matrix or Film modifiers, solubilizers, pH modifiers, lubricants and flow aids, replenishment coatings and density modifiers [84]. Suitable inert additives include dibasic calcium phosphate, ethylcellulose, methacrylate copolymer polyamide, polyethylene, polyvinyl acetate. Suitable fat additives include carnauba wax, acetyl alcohol, hydrogenated vegetable oil, microcrystalline wax, mono- and triglycerides, PEG monostearate and PEG. Suitable hydrophilic additives include alginate, carbopol, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose and methylcellulose [84].

In one embodiment of the present invention, the composition comprising taksen and ritonavir may be formulated so that the ritonavir is released earlier or earlier than the taksen. This will have the effect of inhibiting the CYP3A4 enzyme in the intestine before a significant amount of the taxane is released from the composition. Therefore, it is believed that the effect of ritonavir on the liver CYP3A4 will reduce the amount of taxane decomposed by the CYP3A4 enzyme before reaching the bloodstream, and will also reduce the metabolism and elimination of the taxane reaching the bloodstream during the early stages of its absorption . This effect is illustrated by FIG. 1, where administration of ritonavir 60 minutes prior to docetaxel shows a tendency to increase oral bioavailability and AUC. Although this result is not statistically significant in Example 2, this trend can be seen.

Taxanes are diterpene compounds derived from plants of Taxus ( yews ). However, some Tapsen are currently produced synthetically. Taxanes inhibit cell division by inhibiting cell division and are used to treat cancer. The term "taxane &quot;, as used herein, refers to all diterpene taxanes, whether naturally produced or artificially produced, whether they are naturally occurring or artificially produced, Functional derivatives and pharmaceutically acceptable salts or esters thereof which bind to tubulin and / or are substrates for CYP3A4. Preferred taxanes are docetaxel, paclitaxel, BMS-275183, a functional derivative thereof and a pharmaceutically acceptable salt or ester thereof. BMS-275183 is a C-3'-t-butyl-3'-Nt-butyloxycarbonyl analog of paclitaxel [83]. The most preferred taxanes are docetaxel, a functional derivative thereof or a pharmaceutically acceptable salt or ester thereof, and in particular derivatives which are substrates for CYP3A4.

Also included within the present invention are derivatives of taxanes including groups that modify physicochemical properties. Therefore, polyalkylene glycols (such as polyethylene glycol) or saccharide conjugates of taxane having improved or modified dissolution properties are included.

The pharmaceutical composition of the present invention may comprise any suitable amount of each of taxane and ritonavir. Preferably, the composition comprises from about 0.1 mg to about 1000 mg of a taxane. Preferably, the composition also comprises from about 0.1 mg to about 1200 mg of ritonavir. The amount of each taxane and ritonavir will depend on the intended frequency of administration of the composition. For example, the composition may be administered three times a day, two times a day, once a day, once every two days, once a week, once every two weeks, once every three weeks, Lt; / RTI &gt; Combinations of such dosage regimens may also be used, for example the composition may be administered once a week or twice a day once every two or three weeks. For example, paclitaxel or docetaxel may be administered on a twice-a-day basis once a week. The above-mentioned general daytime administration is divided, and the subject, for example, takes one half of the dose once a week in the morning and the other half in the evening. This has the effect of reducing the drug peak concentration in the blood which can help to reduce side effects. This also increases the overall time of systemic exposure of the drug.

If the composition is to be administered daily, the composition will preferably contain from about 0.1 mg to about 100 mg of a taxane, more preferably from about 5 mg to about 40 mg of taxane, more preferably from about 5 mg to about 30 mg of taxane, To about 20 mg of taxane and most preferably about 15 mg of taxane. Preferably, the composition also comprises about 50 mg to about 1200 mg of ritonavir, more preferably about 50 mg to about 500 mg of ritonavir, more preferably about 50 mg to about 200 mg of ritonavir, and most preferably about 100 mg of ritonavir Includes ritonavir.

If the composition is administered weekly, the composition preferably comprises from about 30 mg to about 500 mg of a taxane, more preferably from about 50 mg to about 200 mg of a taxane, and most preferably about 100 mg of a taxane. Preferably, the composition also comprises about 50 mg to about 1200 mg of ritonavir, more preferably about 50 mg to about 500 mg of ritonavir, more preferably about 50 mg to about 200 mg of ritonavir and most preferably about 100 mg of ritonavir Includes Navier.

Surprisingly, it has been found that the use of ritonavir at a low concentration, for example 100 mg, still has the desirable properties of enhanced bioavailability of the Takken, which provides an enhanced therapeutic effect. This means that a small amount of ritonavir may have a desirable effect, while it can be used to reduce the risk of side effects.

The present invention also provides a therapeutic composition comprising a CYP3A4 inhibitor, such as taxane and ritonavir.

In addition, the present invention also provides a composition for the treatment of a tumorous condition comprising a CYP3A4 inhibitor such as taxane and ritonavir.

The neoplastic disorder to be treated by the present invention is preferably a solid tumor. The solid tumor is preferably selected from the group consisting of breast, lung, stomach, colon, rectum, head and neck, esophagus, liver, kidney, pancreas, bladder, prostate, testis, uterus, endometrium, non-Hodgkin's lymphoma, NHL). The solid tumor is more preferably selected from breast, ovary, prostate, stomach, head and neck, and non-small cell lung cancer.

In one embodiment, the treatment of such a neoplastic disease includes administration of the composition and subsequent administration of a further dose of ritonavir following a predetermined time. The additional amount is preferably from about 0 hours to about 12 hours after the administration of the composition, more preferably from about 1 hour to about 10 hours after the administration of the composition, more preferably from about 2 hours to about 8 hours after administration of the composition, About 3 hours to about 5 hours after administration of the composition and most preferably about 4 hours after administration of the composition. The additional amount is preferably about 50 mg to about 1200 mg of ritonavir, more preferably about 50 mg to about 500 mg of ritonavir, more preferably about 50 mg to about 200 mg of ritonavir, and most preferably about 100 mg of ritonavir It is naive.

Surprisingly, it has been found that the administration of an additional dose of ritonavir provides a therapeutic effect of the taxane for a prolonged period in the bloodstream, resulting in a higher therapeutic effect.

In a related aspect, the present invention also provides a method of treating a tumorous condition, comprising administering to a subject in need of such treatment an effective amount of a CYP3A4 inhibitor such as Taxane and Ritonavir.

Like the above composition, the Tapsen can be any suitable tablet. Preferably, the taxane is selected from docetaxel, paclitaxel, BMS-275183, a functional derivative thereof and a pharmaceutically acceptable salt or ester thereof, more preferably the taxane is selected from docetaxel, a functional derivative thereof or a pharmaceutically Acceptable salts or esters.

When tuxedes and ritonavir are administered to a subject, they can be administered substantially simultaneously with each other. Alternatively, they can be administered separately from each other. When they are administered separately, the ritonavir is preferably administered before the texan, more preferably about 60 minutes before administration of the texan.

As used herein, "substantially simultaneously" means that the administration of tex- ton or ritonavir is within about 20 minutes, more preferably within 15 minutes, more preferably within 10 minutes, even more preferably within 5 minutes , Most preferably within 2 minutes. Generally, the ritonavir should be administered at the same time as or before the administration of the taxane. In some embodiments, the ritonavir and the taxane may be administered simultaneously, i. E. In a single formulation, or simultaneously in two separate formulations.

Any suitable amount of taxane or ritonavir may be administered according to the above method. The amount of taxane and / or ritonavir may be administered in a flat dose (i. E. The same for all patients regardless of body weight or body surface area) or a weight-based or body surface area based administration. Preferably, the taxane and / or ritonavir are administered in a flat dose. Preferably, from about 0.1 mg to about 1000 mg of the taxane is administered. Preferably, from about 0.1 mg to about 1200 mg of ritonavir is administered. The amounts of each taxane and ritonavir will depend on the intended frequency of administration of tex- ton and ritonavir. For example, the composition may be administered three times a day, two times a day, once a day, once every two days, once a week, once every two weeks, once every three weeks, Lt; / RTI &gt; Combinations of such dosage regimens may also be used, for example the composition may be administered once a week or twice a day once every two or three weeks.

Preferably, from about 0.1 mg to about 100 mg of the taxane is administered, more preferably from about 5 mg to about 40 mg of the taxane is administered, and more preferably from about 5 mg to about 100 mg of the taxane is administered, if the method includes daily administration of taxanes and ritonavir About 30 mg of the taxane is administered, more preferably about 10 mg to about 20 mg of the taxane is administered, and most preferably about 15 mg of the taxane is administered. Preferably, about 50 mg to about 1200 mg of ritonavir is administered, more preferably about 50 mg to about 500 mg of ritonavir is administered, more preferably about 50 mg to about 200 mg of ritonavir is administered, 100 mg of ritonavir is administered.

Preferably, about 30 mg to about 500 mg of the taxane is administered, more preferably about 50 mg to about 200 mg of the taxane is administered, and most preferably about 100 mg of the taxane is administered to the patient, if the method includes daytime administration of Taxanes and ritonavir, Lt; / RTI &gt; Preferably, about 50 mg to about 1200 mg of ritonavir is administered, more preferably about 50 mg to about 500 mg of ritonavir is administered, more preferably about 50 mg to about 200 mg of ritonavir is administered, 100 mg of ritonavir is administered.

The method may be for the treatment of any neoplastic disease. Preferably, the tumorous disease is a solid tumor. Preferably, the solid tumor is selected from the group consisting of breast, lung, stomach, colon, rectum, esophagus, liver, kidney, pancreas, bladder, prostate, testes, uterus, endometrium, ovarian cancer and non-Hodgkin's lymphoma , NHL). More preferably, the solid tumor is selected from breast, ovarian, prostate, gastric, head and non-small cell lung cancer.

Preferably, the method is used to treat a human.

In one embodiment, the method further comprises the administration of a further amount of a CYP3A4 inhibitor such as ritonavir at a predetermined time after a first dose of ritonavir (i.e., a dose of ritonavir in combination with a dose of texan). The additional amount is preferably from about 0 hours to about 12 hours after the administration of the composition, more preferably from about 1 hour to about 10 hours after the administration of the composition, more preferably from about 2 hours to about 8 hours after administration of the composition, About 3 hours to about 5 hours after administration of the composition and most preferably about 4 hours after administration of the composition. The additional amount is preferably about 50 mg to about 1200 mg of ritonavir, more preferably about 50 mg to about 500 mg of ritonavir, more preferably about 50 mg to about 200 mg of ritonavir, and most preferably about 100 mg of ritonavir It is naive.

The present invention also provides a method of treating a tumorous disease comprising administering a composition comprising a taxane and one or more pharmaceutically acceptable excipients to a subject receiving a CYP3A4 inhibitor such as ritonavir, &Lt; / RTI &gt;

The invention further provides a method of treating a tumorous condition comprising administering a composition comprising a CYP3A4 inhibitor such as ritonavir and one or more pharmaceutically acceptable excipients simultaneously with a CYP3A4 inhibitor such as ritonavir, To a subject who has been treated with Taxacene.

Additionally, the present invention comprises a first pharmaceutical composition comprising a taxane and a second pharmaceutical composition comprising a CYP3A4 inhibitor such as ritonavir, wherein said first and second pharmaceutical compositions comprise a species A kit suitable for simultaneous, separate or sequential administration for the treatment of benign diseases is provided.

In one embodiment, the kit may further comprise a third pharmaceutical composition comprising a CYP3A4 inhibitor, such as ritonavir, suitable for administration following the second pharmaceutical composition comprising a CYP3A4 inhibitor such as ritonavir . In this kit, the second and third pharmaceutical compositions, each comprising a CYP3A4 inhibitor such as ritonavir, can be in a unit dosage form of the same composition.

Alternatively, the kit may comprise a first pharmaceutical composition comprising a CYP3A4 inhibitor such as Taxane and Ritonavir for the treatment of a tumorous disease. In this case, the kit may further comprise a second pharmaceutical composition comprising a CYP3A4 inhibitor, such as ritonavir, suitable for administration following the first pharmaceutical composition.

Further, the present invention provides a composition for treating a tumorous condition comprising a taxane and at least one pharmaceutically acceptable excipient, wherein the taxane is administered simultaneously or concurrently with a CYP3A4 inhibitor such as ritonavir.

Furthermore, the present invention relates to a pharmaceutical composition comprising a CYP3A4 inhibitor such as ritonavir and at least one pharmaceutically acceptable additive, wherein said CYP3A4 inhibitor is administered simultaneously or simultaneously with said CYP3A4 inhibitor, such as ritonavir, Lt; / RTI &gt;

Any one or all of the above-described preferred features with respect to the composition kit, method kit to which ritonavir is introduced can be selected from grape juice or St. Jihn's wort (or one of these), lopinavir, Or other CYP3A4 inhibitors, e. G. Imidazole compounds such as ketoconazole, may be equallyapplicable to those skilled in the art.

Another problem associated with the prior art is that it has not been possible to develop an oral composition that contains a high bioavailability texene with low variability. Clinical trials of oral paclitaxel [eg, 3] and oral docetaxel [eg, 75] have been reported to be effective in the treatment of patients with chronic hepatitis C ) Was orally administered. Nausea, vomiting and unpleasant taste were often reported to patients.

As discussed earlier, Chen et al. [95] attempted to use solid dispersion of docetaxel in combination with poloxamer 188 or PVP-K30 to improve the solubility and dissolution rate of docetaxel . When the ratio of docetaxel to poloxamer was used at 5:95, the poloxamer increased the solubility of docetaxel to about 3.3 μg / ml after 20 minutes and increased to a maximum of about 5.5 μg / ml after about 120 minutes 7 of FIG. PVP-K30 increased the solubility of docetaxel to about 0.8 μg / ml after 20 minutes and increased to a maximum of about 4.2 μg / ml after about 300 minutes (see FIG. 2). To achieve good oral bioavailability, the drug should have a relatively high solubility and dissolution rate, so there is a high enough amount of drug in the solution with the initial about 0.5 to 1.5 hours.

In another aspect, the invention provides a solid pharmaceutical composition for oral administration comprising a substantially amorphous, tacky, hydrophilic, and preferably polymeric carrier and a surfactant.

The advantage provided by the composition of this aspect is that the solubility of the Takken is increased to a surprising degree. Furthermore, the dissolution rate of the Takken is also increased remarkably. These two factors lead to a meaningful increase in the bioavailability of Tapsan. This was thought to be due, at least in part, to the existence of the Tapsen in amorphous form. Crystalline linseed has very low solubility. Further, in clinical trials, it has been found that the oral compositions of the present invention provide significantly lower individual-internal variability than the high AUC and inter-individual variability exhibited by liquid formulations. This provides highly desirable and more predictable toxin exposure in terms of safety in oral chemotherapy. Individual-intra-individual variability was also significantly lower. An additional advantage is that the oral composition of the present invention appears to be at least equal or more tolerable (i. E., In terms of side effects) than a liquid oral &lt; / RTI &gt;

The advantage provided by the carrier is that it helps keep the Tapsen in amorphous state when present in aqueous media. This helps prevent the takken from being crystallized or increase the length of time before takken begins crystallization in solution. Therefore, the solubility and dissolution rate of the Takken remain high. Furthermore, the carrier provides excellent physical and chemical stability to the composition. This helps to inhibit the decomposition of the Takken and also helps to prevent the substantially amorphous Toksten from changing to a more crystalline structure over time in the solid state. The excellent physical stability ensures that the solubility of the Takken is maintained high.

Surfactants also help keep the tacken in amorphous state when present in aqueous media, and, surprisingly, increase the solubility of the tacken compared to compositions comprising substantially amorphous taxane and carrier.

The term " substantially amorphous "means that there should be little or no long range order of the texant molecular state. The majority of molecules should not be nearly oriented. A completely amorphous structure has no long-range order and does not contain any crystalline structure; This is the opposite of cristalline solids. However, it may be nearly impossible to obtain a completely amorphous structure in some solids. Thus, many "amorphous" structures are not completely amorphous, but still contain a certain amount of long-range order or crystalline crystallinity. For example, solids can be predominantly amorphous, but they are close to true amorphous because they can have crystals of pores or contain very small crystals. The term "substantially amorphous" therefore includes solids which have some amorphous solids but also have some crystalline structure. The crystallinity of the substantially amorphous Toksten should be less than 50%. Preferably, the crystallinity of the substantially amorphous Toksten is less than 40%, more preferably less than 30%, even more preferably less than 25%, even more preferably less than 20%, even more preferably less than 15% , Even more preferably less than 12.5%, even more preferably less than 10%, even more preferably less than 7.5%, even more preferably less than 5% and most preferably less than 2.5%. Since crystalline lintaxene has low solubility, the lower the crystallinity of the substantially amorphous laxan, the better the solubility of the substantially amorphous laxan.

A substantially amorphous Toksten can be made by any suitable method and technique that will be apparent to those skilled in the art. For example, it can be prepared using a solvent evaporation method or lyophilisation. Surprisingly, it has been found that the preparation of amorphous taxanes using freeze drying results in compositions having better solubility and dissolution rate than the evaporation process. It was thought that the freeze drying method would produce more amorphous Toksten than the solvent evaporation method.

Compositions for oral administration are solid. The solid composition may be of any suitable type as long as the Takken is substantially amorphous. For example, the composition may comprise a physical mixture of an amorphous taxane, a carrier and a surfactant. Preferably, the taxane and the carrier are in solid dispersion form. The term " solid dispersion "is well known to those skilled in the art, which means that the taxane is partially molecularly dispersed in the carrier. More preferably, the taxane and the carrier are in solid solution form. The term "solid solution" is well known to those skilled in the art, which means that the tacken is substantially completely molecularly dispersed in the carrier. The solid solution was considered to be substantially more amorphous than solid dispersion. Methods for making solid dispersions and solid solutions are well known to those skilled in the art [93,94]. Using this method, both the taxane and the carrier are amorphous. When the taxane and the carrier are in a solid dispersion or solid solution form, the solubility and dissolution rate of the taxane is higher than the physical mixture of the amorphous taxane and the carrier. When the Tapsen was a solid dispersion or a solid solution, the Tapsen was considered to be more amorphous than the case of itself being amorphous, Toksten. Which was believed to result in improved solubility and dissolution. The crystallinity of the solid dispersion or solid solution should be less than 50%. Preferably, the crystallinity of the solid dispersion or solid solution is less than 40%, more preferably less than 30%, even more preferably less than 25%, even more preferably less than 20%, even more preferably less than 15% , More preferably less than 12.5%, even more preferably less than 10%, even more preferably less than 7.5%, even more preferably less than 5% and most preferably less than 2.5%.

When the surfactant and the carrier are in solid dispersion, the surfactant may be in the form of a solid dispersion or a physical mixture with the solid solution. Preferably, however, the composition comprises the taxane, the carrier and the surfactant in solid dispersion or more preferably in solid solution form. The advantage of having all three components in a solid dispersion or solid solution is that smaller amounts of surfactants can be used to achieve the same improvements in solubility and dissolution rate.

In one embodiment, the composition may be included in a capsule for oral administration. The capsule can be filled in a number of different ways. For example, the amorphous taxanes can be prepared by lyophilization, powdering, admixture with carriers and surfactants, and then into the capsules. In an optional preferred embodiment, the amorphous taxane is prepared by lyophilization of a taxane solution in a capsule for oral administration. The taxane solution containing the required amount of the taxane is injected into the capsule, unlike that contained in the capsule, and then lyophilized. This makes it easier to dispense the amount of Takken needed into the capsule because it is easier to inject liquid than the powder. This also makes the process more efficient by eliminating the capsule filling step. A powdered carrier and a surfactant are then added. Preferably, the capsule is an HPMC capsule.

If the taxane and the carrier are in the form of a solid dispersion or a solid solution, the solution containing the taxane and the carrier is preferably injected into the capsule and then lyophilized in the capsule. In this method, the solid dispersion or solid solution is prepared by lyophilization of the solution of the taxane and the carrier in capsules for oral administration. This removes the capsule filling step again. A powdered surfactant is then added.

If the taxane, carrier and surfactant are in solid dispersion or solid solution form, the solution comprising the taxane, the carrier and the surfactant is preferably injected into the capsule and then lyophilized in the capsule. In this method, the solid dispersion or solid solution is prepared by lyophilization of a solution of the taxane, carrier and surfactant in a capsule for oral administration. This removes the capsule filling step again and eliminates the need to deal with powder that may be a problem.

The taxane of the composition may be any suitable taxane as defined above. Preferably, the taxane is selected from docetaxel, paclitaxel, BMS-275183, a functional derivative thereof and a pharmaceutically acceptable salt or ester thereof. More preferably, the taxane is selected from docetaxel, paclitaxel, a functional derivative thereof and a pharmaceutically acceptable salt or ester thereof.

The hydrophilic and preferably polymeric carrier of the composition is an organic, more preferably a polymeric, compound which enables at least partial dissolution in an aqueous medium at pH 7.4 and / or allows swelling or gelling in such an aqueous medium. The carrier can be any suitable hydrophilic and preferably polymeric carrier, such that the tacken remains amorphous in the composition and increases the solubility and dissolution rate of the tacken. Preferably, the carrier is selected from: polyvinylpyrrolidone (PVP); Polyethylene glycol (PEG); Polyvinyl alcohol (PVA); Crospovidone (PVP-CL); Polyvinylpyrrolidone-polyvinylacetate copolymers (PVP-PVA); Cellulose derivatives such as methylcellulose, hydroxypropylcellulose, carboxymethylethylcellulose, hydroxypropylmethylcellulose (HPMC), cellulose acetate phthalate and hydroxypropylmethylcellulose phthalate; Polymethacrylate; Party; Polyols and their polymers such as mannitol sucrose, sorbitol, dextrose and chitosan; And cyclodextrins. More preferably, the carrier is PVP, PEG and HPMC, and most preferably, the carrier is PVP.

If the carrier is PVP, it can be any suitable PVP that acts as a carrier and can help keep the Tapsen in amorphous state. For example, the PVP may be selected from PVP-K12, PVP-K15, PVP-K17, PVP-K25, PVP-K30, PVP-K60, PVP-K90 and PVP-K120. Preferably, the PVP is selected from PVP-K30, PVP-K60 and PVP-K90.

The composition may comprise any suitable amount of carrier as opposed to an amorphous taxane, so that the carrier maintains the amorphous taxane in an amorphous state. Preferably, the weight ratio of the taxane and the carrier is from about 0.01: 99.99 w / w to about 75:25 w / w. More preferably, the weight ratio of the taxane and the carrier is from about 0.01: 99.99 w / w to about 50:50 w / w, more preferably from about 0.01: 99.99 w / w to about 40:60 w / w, More preferably from about 0.01: 99.99 w / w to about 30:70 w / w, even more preferably from about 0.1: 99.9 w / w to about 20:80 w / w, even more preferably from about 1: w / w to about 20:80 w / w, even more preferably from about 2.5: 97.5 w / w to about 20:80 w / w, even more preferably from about 2.5: 97.5 w / : 85 w / w, even more preferably from about 5:95 w / w to about 15:85 w / w, and most preferably about 10:90 w / w.

The surfactant may be any pharmaceutically acceptable surfactant and such surfactants are well known to those skilled in the art. Preferably, the surfactant is selected from the group consisting of triethanolamine, sunflower oil, stearic acid, monobasic sodium phosphate, sodium citrate dihydrate, propylene glycol alginic acid, oleic acid, monoethanolamine, mineral oil and lanolin alcohol, methylcellulose, But are not limited to, lecithin, lecithin, hydrous lanolin, lanolin, hydroxypropylcellulose, glyceryl monostearate, ethylene glycol pamitostearate, diethanolamine, lanolin alcohol, cholesterol, cetyl alcohol, cetostearyl alcohol Castor oil, sodium dodecylsulfate (SDS), sorbitan ester (sorbitan fatty acid ester), polyoxyethylene stearate, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil derivative, polyoxyethylene Ethylene alkyl ether, poloxamer (pol oxamer, glyceryl monooleate, docusate sodium, cetrimide, benzyl benzoate, benzalkonium chloride, benzethonium chloride, hypromellose, non-ionic emulsion Emulsifying wax, anionic emulsifying wax, and triethyl citrate. More preferably, the surfactant is selected from the group consisting of sodium dodecylsulfate (SDS), sorbitan ester (sorbitan fatty acid ester), polyoxyethylene stearate, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil derivative, poly But are not limited to, oxyethylene alkyl ethers, poloxamers, glyceryl monooleate, docusite sodium, cetrimide, benzyl benzoate, benzalkonium chloride, benzethonium chloride, hypromelose, non- Anionic emulsifying wax and triethyl citrate. Most preferably, the surfactant is SDS.

Any suitable amount of surfactant may be used in the composition to improve the solubility and dissolution rate of the taxane. Preferably, the weight ratio of the taxane and the carrier combined with the surfactant is from about 1:99 w / w to about 50:50 w / w, more preferably from about 1:99 w / w to about 44:56 w / w , More preferably from about 1:99 w / w to about 33:67 w / w, even more preferably from about 2:98 w / w to about 33:67 w / w, even more preferably from about 2: W / w to about 17:83 w / w, even more preferably from about 5:95 w / w to about 17:83 w / w, and most preferably about 9:91 w / w.

Alternatively, the weight ratio of surfactant to taxane is preferably from about 1: 100 w / w to about 60: 1 w / w, more preferably from about 1:50 w / w to about 40: 1 w / w, W / w to about 20: 1 w / w, even more preferably from about 1:10 w / w to about 10: 1 w / w, even more preferably from about 1: 5 w / w / w to about 5: 1 w / w, even more preferably from about 1: 3 w / w to about 3: 1 w / w, even more preferably from about 1: 1 w / w, and most preferably about 1: 1 w / w.

The unit dose of the taxane contained in the composition will depend on the intended frequency of administration of the composition. Appropriate dosages and frequency of administration are discussed above with regard to the tex- and ritonavir compositions.

In one embodiment, the composition comprises an enteric coating. A suitable working coating is described above. The enteric coating prevents the release of Tapsene from the top, thus preventing the acid-mediated degradation of Tapsen. Moreover, this allows targeted transmission of the Tapsene to the intestine where the Tapsene is absorbed, so that the limited time during which the Tapsene is present in solution (before the crys- tallylation occurs) is taken only at the site where absorption is possible.

In one embodiment, the composition may further comprise one or more additional pharmaceutically active ingredients. Preferably, the additional pharmacologically active ingredient is a CYP3A4 inhibitor. Suitable CYP3A4 inhibitors are discussed above. Preferably, the CYP3A4 inhibitor is ritonavir.

Such pharmaceutical compositions include additional pharmaceutically acceptable adjuvants and vehicles well known to those skilled in the art. Pharmaceutically acceptable adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, serum proteins such as human serum albumin, buffer components such as phosphate, Glycerin, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or protamine sulfates, disodium hydrogenphosphate, potassium hydrogenphosphate, sodium But are not limited to, electrolytes such as chloride, zinc salts, colloidal silica, magnesium trisilicate, and wool fat.

The pharmaceutical composition may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, powders or coated granules. Tablets may be formulated with immediate release, slow release, repeated release or delayed release. They may also, or alternatively, be effervescent, bilayer and / or coated tablets. Capsules may be formulated to be immediate, sustained, repeated release or delayed release. Lubricants such as magnesium stearate are also typically added. Useful diluents in capsule form for oral administration include lactose and dried corn starch. Other pharmaceutical additives that may be added for tablets and capsules are binders, fillers, fillers / binders, adsorbents, wetting agents, disintegrants, lubricants, glidants, and the like. Tablets and capsules may be coated to change the appearance or properties of tablets and capsules, for example, to change the taste of tablets or capsules, or to coat a coating color.

Other pharmaceutically acceptable additives that may be added to the composition are well known to those skilled in the art, some of which are discussed above in connection with the composition according to the first aspect of the present invention.

The present invention also provides such compositions for use in therapy.

In addition, the present invention provides such a composition for use in the treatment of a tumorous disease. Suitable tumorigenic diseases are discussed above.

The present invention also provides a method of treating a tumorous condition, said method comprising administering an effective amount of said composition to a subject in need of such treatment.

Preferably, the method is used to treat a human.

It will be appreciated by those skilled in the art that the compositions of the present invention comprising substantially amorphous taxane and carrier can be used in the methods described above where appropriate in connection with the use of Taxanes and CYP3A4 inhibitors or ritonavir.

In another aspect, the present invention provides a pharmaceutical composition for oral administration comprising a substantially amorphous taxane and a carrier, wherein the substantially amorphous taxane is prepared by lyophilization.

The advantage provided by this composition is that it provides increased solubility of the taxane and also an increased dissolution rate. This is thought to be due to the fact that the freeze-drying method produces a more amorphous taxane compared to other methods of producing amorphous taxanes. The more amorphous nature of the Takken was thought to provide increased solubility and dissolution rate.

Additional and optional features of the composition are the same as those of the composition comprising an amorphous taxane, a carrier and a surfactant. For example, the composition comprising a substantially amorphous taxane and a carrier preferably further comprises a surfactant, wherein the substantially amorphous taxane is prepared by lyophilization. A preferred embodiment of the above-described preferred embodiment of the present invention is that of the above-described preferred embodiments, such as a taxane, a carrier, a crystal lattice of a taxane, a ratio of a taxane and a carrier,

Example  One

A 100 mg ritonavir dose was combined with a 100 mg dose of docetaxel and administered orally to 22 patients. The comparison subjects were intravenous docetaxel (100 mg) (Taxotere ^® ) (without ritonavir) given for 1 hour iv infusion (standard procedure).

Oral ritonavir: 1 capsule containing 100 mg of ritonavir (Norvir ^® ). Oral docetaxel Dose: 100 mg. Commercially available intravenously administered docetaxel formulation (takso terephthalate ^{® (Taxotere ®); 2ml =} 80mg docetaxel; additives polysorbate 80) ethanol 95%: water (13: 87) is diluted with drinking the patient with the 100ml water 10 mg / ml docetaxel solution (10 ml of 10 mg / ml solution).

The pharmacokinetic data obtained are as follows:

In the absence of ritonavir, oral docetaxel AUC 0.29 ± 0.26 (mg.h / L)

Oral docetaxel AUC 2.4 ± 1.5 (mg.h / L) with ritonavir

In the absence of ritonavir, venous docetaxel AUC 1.9 ± 0.4 (mg.h / L)

The results show a double effect of ritonavir on both docetaxel uptake and elimination. Docetaxel AUC increases 8.2-fold when given orally in combination with ritonavir. Surprisingly, the exposure is much higher than that reached after intravenous administration, reflecting the effect of additional ritonavir to block the removal of docetaxel.

conclusion

The notion that the ritonavir can increase the systemic exposure of oral docetaxel to a higher or similar level compared to the level after intravenous administration of docetaxel at the same dose level is clearly demonstrated in patients. The combination appears to be safe with very favorable pharmacokinetic characteristics.

Example  2

Treatment of solid malignant tumors by combination of oral docetaxel and ritonavir

Patients were randomized into two treatment groups, X and Y. Group X received 100 mg of ritonavir in the first week, 100 mg of oral docetaxel in 60 minutes, and 100 mg of ritonavir and 100 mg of oral docetaxel in the second week. Group Y patients received 100 mg ritonavir and 100 mg oral docetaxel in the first week, 100 mg docetaxel in the second week, and 100 mg oral docetaxel in 60 minutes. Both Groups X and Y received 100 mg intravenously dosed docetaxel (Taxotere ^® ; standard course; 1 hour infusion) for 15 days after the start of oral administration without ritonavir.

Oral docetaxel Dose: 100 mg. Commercially available intravenously administered docetaxel formulation (takso terephthalate ^{® (Taxotere ®); 2ml =} 80mg docetaxel; additives polysorbate 80) ethanol 95%: water (13: 87) is diluted with drinking the patient with the 100ml water 10 mg / ml docetaxel solution (10 ml of 10 mg / ml solution). Ritonavir dose: 1 capsule containing 100mg of ritonavir eoga (Nord builder ^® (Norvir ^®)).

Pharmacokinetic results are given below:

Doclex patient AUC (mg x h / L) F (%) ¹ The same time Every 60 minutes Intravenous administration 15 days The same time Every 60 minutes 101 (X) 5.6 4.1 1.7 329 241 102 (Y) 1.6 2.6 1.8 89 144 103 (Y) 2.2 4.6 1.8 122 256 105 (X) 2.8 3.3 2.1 133 157 106 (Y) 2.4 3.9 1.4 171 279 107 (Y) 2.4 2.1 2.6 92 81 108 (X) 1.1 1.4 1.4 79 100 110 (X) 0.7 0.6 2.2 32 27 Mean ± SD 2.4 ± 1.5 2.8 ± 1.4 1.9 ± 0.4 131 ± 90 161 ± 91

¹ F (clear) is determined as (AUC _po / AUC _iv ) × (dose _iv × dose _po ) × 100%.

Doclex patient Cmax (mg / L) Tmax (h) The same time Every 60 minutes Intravenous administration 15 days The same time Every 60 minutes Intravenous administration 15 days 101 (X) 0.71 0.58 1.47 3.3 3.0 1.0 102 (Y) 0.21 0.42 1.52 4.0 2.0 1.0 103 (Y) 0.20 0.72 1.3 4.0 3.0 0.8 105 (X) 0.36 0.34 1.6 4.0 4.0 1.0 106 (Y) 0.42 0.91 1.1 2.0 2.0 0.8 107 (Y) 0.26 0.50 1.5 3.0 1.5 1.0 108 (X) 0.26 0.19 1.0 2.1 3.0 0.8 110 (X) 0.10 0.11 1.6 1.0 1.5 0.8 Mean ± SD 0.32 ± 0.2 0.47 ± 0.3 1.4 ± 0.2 2.9 ± 1.1 2.5 ± 0.9 0.9 ± 0.1

conclusion

Concomitant administration of docetaxel and ritonavir is not significantly different from administration of ritonavir 60 minutes prior to docetaxel administration. The AUC of oral administration is greater than the AUC of intravenous administration (see FIG. 1). This is explained by the effect of ritonavir which inhibits the removal of docetaxel.

comment

This study was performed with relatively low doses of docetaxel, but it has a higher AUC value (2.4 ± 1.5 mg.h / L; 100 mg docetaxel) and is much higher than the AUC value after intravenous administration of the same dose. In addition, it has been shown that the distribution volume after oral route is larger (short after administration) than after intravenous route because the pharmaceutical vehicle limits the tissue distribution of docetaxel, which is present after intravenous administration but does not reach the systemic circulation after oral administration It is realized. The inventors have made a pharmacokinetic model to understand this effect (see below). The model also shows that the effect of ritonavir on the removal of docetaxel disappears when ritonavir is no longer present in the bloodstream. Ritonavir inhibits the clearance of docetaxel to 35% of its value in the absence of ritonavir.

Compared with the doses used in the prior art preclinical studies on mice, 12.5 mg / kg of ritonavir and 10-30 mg / kg of docetaxel were used in preclinical studies on the rats, whereas in this trial 100 mg of ritonavir and 100 mg docetaxel was used. For humans 10-30 mg / kg of docetaxel is extremely toxic (life threatening). A dose of 12.5 mg / kg of ritonavir is generally significantly higher than that used to inhibit CYP3A4 in humans.

In prior art preclinical studies, ritonavir was given 30 minutes before docetaxel was given. In this clinical trial, the drug was administered concurrently with no significant difference in docetaxel pharmacokinetic improvement between when the drug was given concurrent with ritonavir and when given 60 minutes before. This indicates that the two drugs may be given as a single pharmaceutical formulation (for example, tablets, capsules or draining solutions containing both docetaxel and ritonavir).

The docetaxel AUC value (2.4 +/- 1.5 mg.h / L) obtained when administered with 100 mg ritonavir (with a dose of 100 mg docetaxel) can be considered therapeutically active in the weekly schedule (e. G., Metastatic Breast cancer). This is due to a weekly schedule of 100 mg docetaxel at a dose of 15 mg / kg orally given with CsA leading to a total response rate of 50% in patients with metastatic breast cancer and a good early phase II trial with docetaxel AUC of about 2.3 mg.h / L do.

The ritonavir pharmacokinetic data is given completely below (see Figure 2):

Ritonavier patient AUC (mg.h / L) Cmax (mg / L) Tmax (h) The same time Every 60 minutes The same time Every 60 minutes The same time Every 60 minutes 101 (X) 23.2 11.8 3.1 1.3 3.3 0.3 102 (Y) 7.3 8.9 0.8 1.1 4.0 0.5 103 (Y) 13.5 14.1 0.7 1.1 6.0 3.0 105 (X) 8.8 9.4 0.6 0.7 6.0 6.0 106 (Y) 13.3 13.4 1.5 1.3 3.0 1.0 107 (Y) 5.2 5.7 0.3 0.8 3.0 0.5 108 (X) 2.6 4.2 0.2 0.5 2.1 2.0 110 (X) 1.9 0.5 0.2 0.03 3.1 1.5 Mean ± SD 9.5 ± 7.0 8.5 ± 4.7 0.9 ± 0.97 0.9 ± 0.44 3.8 ± 1.4 1.9 ± 1.9

Pharmacokinetic profile

Pharmacokinetic (PK) analysis of the data generated in the test was performed using a NONMEM (non-linear mixed effect modeling) program (GloboMax LLC, Hanover, MD, USA) to generate a pharmacokinetic profile. This models the absorption, elimination and distribution of drugs using different moieties. Pharmacological differences between oral and intravenous administration are shown below.

Oral docetaxel exposure was tested following administration of a single dose of docetaxel alone and in combination with ritonavir. Ritonavir was administered simultaneously or 1 hour before oral docetaxel.

After drug administration, blood samples were taken for pharmacokinetic analysis. Bone samples were obtained prior to dosing. Blood samples were centrifuged and the plasma separated and stored immediately at -20 ° C until analysis. The analysis was carried out by an approved HPLC method in a GLP (Good Laboratory Practice) approved laboratory. This relates to all pharmacokinetic studies shown here by the inventors.

PK  Model

The PK model was based on the PK model of iv docetaxel. This model uses three parts and is well described in Bruno et al. [85]. Data generated from orally administered docetaxel was performed in this model with the addition of an additional depot portion for the gastrointestinal track. The pharmacokinetic model for ritonavir was best described using the two partial models described in Capelhof et al. [87]. Figure 3 diagrammatically shows the final pharmacokinetic model. The effects of ritonavir on the pharmacokinetics of docetaxel were modeled following two different mechanisms: a) uptake of docetaxel in the presence of ritonavir (conjugation of docetaxel uptake from C1 to C2 and ritonavir (RTV) line); b) Ritonavir inhibits active CYP3A4 (a line connecting C6 and C7) and active CYP3A4 causes the removal of docetaxel (a line connecting the docetaxel removal pathway with C7).

absorption

The absorption of docetaxel was significantly enhanced when administered with ritonavir. The calculated bioavailability of oral docetaxel alone was 14% (based on data from three patients who received 100 mg oral docetaxel). The bioavailability of oral docetaxel combined with ritonavir was 56%, four times higher. This effect may be due to inhibition of the CYP3A4 enzyme in the gastrointestinal track by ritonavir.

remove

Docetaxel is metabolized mainly by CYP3A4. Ritonavir inhibits CYP3A4. This results in reduced elimination when ritonavir is administered with docetaxel. The clearance of docetaxel correlates with the amount of CYP3A4 and therefore varies across time. Figure 4 shows the relative enzyme concentration estimated over the entire time. The clearance of docetaxel has a 1: 1 correlation with enzyme concentration. Therefore, a graph of the clearance versus time of docetaxel will be similar to FIG.

Distribution volume

The volume of the central portion (C2 in Figure 3) is noticeably different between iv (+/- 6L) and oral (+/- 60L) dosing. This is probably due to Polysorbate 80, which is one of the main additives in docetaxel formulations. Polysorbate 80 forms micelles capable of containing docetaxel [86]. Polysorbate 80 enters the circulation for iv administration but is not absorbed for oral administration. Therefore, the polysorbate does not affect the pharmacokinetic behavior of docetaxel after oral administration due to the fact that it is not absorbed.

conclusion

The oral bioavailability of docetaxel increased approximately four-fold when administered with ritonavir. Systemic exposures increased 8.2-fold (ie, absorbed and eliminated, respectively), in terms of AUC, due to the combined effect of ritonavir on CYP3A4 in the gastrointestinal track and liver.

When combined with ritonavir, removal of docetaxel is reduced.

The distribution volume (volume of the central portion) is small when polysorbate 80 is present, and large when no polysorbate is present.

Diluted with 10 ethanol 95% commercially available intravenously administered docetaxel formulation (additive polysorbate 80 takso terephthalate ^{® (Taxotere ®);; 2ml} = 80mg docetaxel) In the above-mentioned oral docetaxel test: water (87 13) mg / ml &lt; / RTI &gt; docetaxel solution. This solution, made by a pharmacist, was orally taken by the patient (10 ml of 10 mg / ml solution for 100 mg administration) with a drinking solution in combination with 100 ml tap water. This is feasible for research purposes, but not for everyday use or household use. The preparation of the dragging solution by a pharmacist takes time. The solution has a limited stability. Patients often complained about the unpleasant and unpleasant taste of the drinking solution (perhaps due to polysorbate and ethanol additive). Obviously, oral solid dosage forms (e. G., Ingested by capsules or tablets) are both friendly and more patient friendly.

In summary, the present invention improves the bioavailability and systemic exposures of texans, improves the clinical efficacy of texas, particularly oral texas, and possibly reduces possible side effects associated with treatment. This is economically and clinically beneficial.

Example  3- Pk  Oral formulation

3.1: solid Dispersion band  Physical mixture

In this test, the solubility and dissolution rate of the composition containing the solid dispersion of paclitaxel and PVP-K17 mixed with SDS was compared with the physical mixture of amorphous pkr-texel, PVP-K17 and SDS.

PVP - K17  of mine Park Litexel Of solid dispersion  5 mg  capsule

Solid dispersion of 20% pk rtaxel in PVP-K17 was prepared by dissolving 100 mg pk rtaxel in 10 mL t-butanol and 400 mg PVP-K17 in 6.67 mL water. The paclitaxel / t-butanol solution was added to the PVP-K17 / water solution with continued stirring. The final mixture was transferred to an 8 mL vial filled to a maximum volume of 2 mL. t-Butanol and water were removed by freeze-drying in succession (see conditions in Table 4). 25 mg of paclitaxel 20% / PVP-K17 solid dispersion (= 5 mg paclitaxel) was mixed with 125 mg lactose, 30 mg sodium dodecylsulfate, and 30 mg croscarmellose sodium. The resultant powder mixture was encapsulated (see Table 5).

Freeze drying conditions: Lyovac GT4 (AMSCO / Finn-Aqua) step Time (hh: mm) Storage temperature (℃) Actual pressure (%) Max Pressure (%) One 00:00 around 100 100 2 01:00 -35 100 100 3 03:00 -35 100 100 4 03:01 -35 40 50 5 48:00 -35 40 50 6 63:00 25 40 50 7 66:00 25 40 50

Formulation of 5 mg paclitaxel / PVP-K17 solid dispersion capsule ingredient Amount (mg) Paclitaxel (in solid dispersion) 5 mg PVP-K17 (in solid dispersion) 20 mg Lactose monohydrate 125 mg Sodium dodecylsulfate 30 mg Croscarmellose sodium 30 mg

PVP - K17 In a physical mixture containing Pk  5 mg  capsule

The physical mixture was prepared by mixing 5 mg amorphous paclitaxel with 20 mg PVP, 125 mg lactose, 30 mg sodium dodecylsulfate and 30 mg croscarmellose sodium. The resultant powder mixture was sealed.

Formulation of 5 mg paclitaxel / PVP-K17 physical mixture capsules ingredient Amount (mg) Park Litexel 5 mg PVP-K17 20 mg Lactose monohydrate 125 mg Sodium dodecylsulfate 30 mg Croscarmellose sodium 30 mg

Dissolution test

Two capsule formulations were tested in a USP2 (paddle) dissolution apparatus with a rotational speed of 75 rpm in 900 mL water for injection while maintaining 37 [deg.] C. In the first experiment, one capsule of each formulation was used. In the second experiment, two capsules of each formulation were used. Samples were collected at several time points and analyzed by HPLC-UV (see Table 5).

Chromatographic conditions column Apex octyl 150 x 4.6 mm 5 m Eluens Methanol / acetonitrile / 0.02M ammonium acetate 1/4/5 v / v / v Flow 1.0 mL / min Injection volume 50 μl Uptime 15 minutes Detection wavelength 227 nm

Results and conclusions

The results are shown in FIG. The amount of dissolved paclitaxel is expressed relative to the label claim (5 and 10 mg). It can be clearly seen that the dissolution of paclitaxel is greatly enhanced by going into solid dispersion with PVP. When a physical mixture is used, the maximum amount of dissolved paclitaxel remains below 20% of the label claim. When solid dispersion is used. The solubility is about 65% (5 mg paclitaxel) or greater than 70% (10 mg paclitaxel). In a 10 mg paclitaxel experiment, this corresponds to an absolute solubility of about 8 g / ml, which is achieved after about 15 minutes. Therefore, the solid dispersion significantly increases solubility and also provides a fast dissolution rate, both of which are important for bioavailability.

In solid solution or solid dispersion, the amorphous state of the carrier enables a complete mixture of the carrier and the taxane. The carrier inhibits crystallization during storage as well as during dissolution in an aqueous medium.

3.2: In the capsule formulation, sodium Dodecyl Of interest  addition

In this experiment, the effect on the solubility in the presence or absence of the surfactant SDS in the capsules was determined.

PVP - K17  My 20% Park Litexel  Solid dispersion

Solid dispersion was prepared by dissolving 400 mg PVP-K17 in 6.67 mL water and 100 mg paclitaxel in 10 mL t-butanol. The paclitaxel / t-butanol solution was added to the PVP-K17 / water solution with continued stirring. The final mixture was transferred to an 8 mL vial filled to a maximum volume of 2 mL. t-Butanol and water were removed by freeze-drying in succession (see Table 4).

Sodium Dodecyl If the  No 5 mg Park Litexel  capsule

25 mg of paclitaxel 20% / PVP-K17 solid dispersion (= 5 mg paclitaxel) was mixed with 125 mg lactose and sealed (see Table 8).

Formulation of 5 mg paclitaxel / PVP-K17 solid dispersion capsule without sodium dodecylsulfate ingredient Amount (mg) Paclitaxel (in solid dispersion) 5 mg PVP-K17 (in solid dispersion) 20 mg Lactose monohydrate 125 mg

Sodium Dodecyl If the  Included 5 mg Park Litexel  capsule

25 mg of paclitaxel 20% / PVP-K17 solid dispersion (= 5 mg paclitaxel) was mixed with 125 mg lactose, 30 mg sodium dodecyl sulphite and 30 mg croscarmellose sodium. The resultant powder mixture was encapsulated (see Table 9).

Formulation of 5 mg paclitaxel / PVP-K17 solid dispersion capsule containing sodium dodecylsulfate ingredient Amount (mg) Paclitaxel (in solid dispersion) 5 mg PVP-K17 (in solid dispersion) 20 mg Lactose monohydrate 125 mg Sodium dodecylsulfate 30 mg Croscarmellose sodium 30 mg

Dissolution test

Two capsule formulations were tested in a USP2 (paddle) dissolution apparatus with a rotational speed of 75 rpm in 900 mL water for injection while maintaining 37 [deg.] C. Samples were collected at multiple time points and analyzed by HPLC-UV (see Table 7).

Results and conclusions

The results are shown in Fig. The amount of dissolved paclitaxel is expressed relative to the label claim (in this case 5 mg). The porosity of the lyophilized pellet and carrier solid dispersion is high enough to allow rapid dissolution when in powder form (results not shown). However, when the powder is compressed into a capsule, the wettability is dramatically reduced. Therefore, surfactants are needed to moisten the solid dispersion when compressed into capsules or tablets.

It can be seen clearly from FIG. 6 that the dissolution of paclitaxel is greatly enhanced by the addition of the surfactant sodium dodecylsulfate. Previous experiments have shown that the addition of croscarmellose sodium, the use of more lactose or larger capsules did not result in an increased dissolution rate of the capsule formulation. Again, this shows that maximum dissolution with surfactants such as SDS is achieved in about 10-15 minutes.

3.3: Addition of sodium Dodecyl Of interest  addition

In this experiment, the effect on solubility by addition of SDS to solid dispersion was determined.

PVP - K17  of mine Park Litexel  40% solids dispersion

Solid dispersion was prepared by dissolving 600 mg paclitaxel in 60 mL t-butanol and 900 mg PVP-K17 in 40 mL water. The paclitaxel / t-butanol solution was added to the PVP-K17 / water solution with continued stirring. The final mixture was transferred to an 8 mL vial filled to a maximum volume of 2 mL. t-Butanol and water were removed by freeze-drying in succession (see Table 4).

PVP - K17  And sodium Dodecyl Welcome  Within 10% Park Litexel  40% solids dispersion

Solid dispersion was prepared by dissolving 250 mg paclitaxel in 25 mL t-butanol, 375 mg PVP-K17 in 16.67 mL water and 62.5 mg sodium dodecylsulfate (SDS). The praklitaxel / t-butanol solution was added to the PVP-K17 / sodium dodecyl sulfite / water solution with constant stirring. The final mixture was transferred to an 8 mL vial filled to a maximum volume of 2 mL. t-Butanol and water were removed by freeze-drying in succession (see Table 4).

Park Litexel / PVP - K17  25 of solid dispersion mg Park Litexel  capsule

62.5 mg of paclitaxel 40% / PVP-K17 solid dispersion (= 25 mg paclitaxel) was mixed with 160 mg lactose, 30 mg sodium dodecyl sulphite and 10 mg croscarmellose sodium. The resultant powder mixture was encapsulated (see Table 10).

Formulation of 25 mg paclitaxel / PVP-K17 solid dispersion capsule ingredient Amount (mg) Paclitaxel (in solid dispersion) 25 mg PVP-K17 (in solid dispersion) 37.5 mg Lactose monohydrate 125 mg Sodium dodecylsulfate 30 mg Croscarmellose sodium 10 mg

Park Litexel / PVP - K17 / Sodium dodecyl Welcome  25 of solid dispersion mg Park Litexel  capsule

68.75 mg of paclitaxel 40% / PVP-K17 / 10% sodium dodecylsulfate solid dispersion (= 25 mg paclitaxel) was mixed with 160 mg lactose and 10 mg croscarmellose sodium. The resultant powder mixture was encapsulated (see Table 11).

Formulation of 25 mg paclitaxel / PVP-K17 solid dispersion capsule ingredient Amount (mg) Paclitaxel (in solid dispersion) 25 mg PVP-K17 (in solid dispersion) 37.5 mg Sodium dodecyl sulphite (in solid dispersion) 6.25 mg Lactose monohydrate 125 mg Croscarmellose sodium 10 mg

Dissolution test

Two capsule formulations were tested in a USP2 (paddle) dissolution apparatus at 37 DEG C in 500 mL of water for injection. The rotation rate was set at 75 rpm for capsules with paclitaxel / PVP-K17 / sodium dodecylsulfate solid dispersion and at 100 rpm for capsules with paclitaxel / PVP-K17 solid dispersion. Samples were collected at multiple time points and analyzed by HPLC-UV (see Table 7).

Results and conclusions

The results are shown in FIG. The amount of dissolved paclitaxel is expressed relative to the label claim (in this case 25 mg). The dissolution of paclitaxel in capsules with sodium dodecyl sulphate introduced into the solid dispersion is similar to that of paclitaxel in capsules with sodium dodecyl sulphate added to the capsules. Furthermore, only 6.25 mg of sodium dodecylsulfate was used for incorporation into the solid dispersion, while 30 mg of sodium dodecylsulfate was used to add to the capsule formulation. This shows that fewer surfactants are needed when introduced into the solid dispersion rather than added into the capsule to achieve a similar result. Another surprising result in this experiment is that both compositions provide an absolute paclitaxel solubility of about 26 μg / ml, which reaches 20-30 minutes. This result provides higher solubility and faster dissolution rate than previously achieved.

3.4: Influence of carrier

The solid dispersion used in the experiment of Example 3.4 produced after the initial experiment did not show a clear difference between the drug loads. A 40% drug loading was selected because these formulations were performed in the same manner as the 20% drug loading in the above-mentioned experiments and provided the possibility of delivering more tablets to one tablet or capsule.

PVP - K12  of mine Park Litexel  40% solids dispersion

Solid dispersion was prepared by dissolving 250 mg paclitaxel in 25 mL t-butanol and 375 mg PVP-K12 in 16.67 mL water. The paclitaxel / t-butanol solution was added to the PVP-K12 water solution with constant stirring. The final mixture was transferred to an 8 mL vial filled to a maximum volume of 2 mL. t-Butanol and water were removed by freeze-drying in succession (see Table 4).

PVP - K17  of mine Park Litexel  40% solids dispersion

Solid dispersion was prepared by dissolving 600 mg paclitaxel in 60 mL t-butanol and 900 mg PVP-K17 in 40 mL water. The paclitaxel / t-butanol solution was added to the PVP-K17 water solution with continued stirring. The final mixture was transferred to an 8 mL vial filled to a maximum volume of 2 mL. t-Butanol and water were removed by freeze-drying in succession (see Table 4).

PVP - K30  of mine Park Litexel  40% solids dispersion

Solid dispersion was prepared by dissolving 250 mg paclitaxel in 25 mL t-butanol and 375 mg PVP-K30 in 16.67 mL water. The paclitaxel / t-butanol solution was added to the PVP-K17 water solution with continued stirring. The final mixture was transferred to an 8 mL vial filled to a maximum volume of 2 mL. t-Butanol and water were removed by freeze-drying in succession (see Table 4).

HP - Cyclodextrin  of mine Park Litexel  40% solids dispersion

Solid dispersion was prepared by dissolving 250 mg paclitaxel in 25 mL t-butanol and 375 mg HP-cyclodextrin in 16.67 mL water. The paclitaxel / t-butanol solution was added to the HP-cyclodextrin water solution with continued stirring. The final mixture was transferred to an 8 mL vial filled to a maximum volume of 2 mL. t-Butanol and water were removed by freeze-drying in succession (see Table 4).

25 mg Park Litexel  Solid dispersion capsule

62.5 mg of paclitaxel / vehicle solid dispersion (= 25 mg paclitaxel) was mixed with 160 mg lactose, 30 mg sodium dodecyl sulphate and 10 mg croscarmellose sodium. The resultant powder mixture was encapsulated (see Table 12).

Formulation of 25 mg paclitaxel / carrier solid dispersion capsule ingredient Amount (mg) Paclitaxel (in solid dispersion) 25 mg PVP-K17 (in solid dispersion) 37.5 mg Lactose monohydrate 125 mg Sodium dodecylsulfate 30 mg Croscarmellose sodium 10 mg

Dissolution test

All capsule formulations were tested in a 500 mL syringe at a rotational speed of 100 rpm while maintaining 37 DEG C in a USP2 (paddle) dissolution apparatus. Samples were collected at multiple time points and analyzed by HPLC-UV (see Table 7).

Results and conclusions

The average results of two to three experiments are shown in FIG. The amount of dissolved paclitaxel is expressed relative to the label claim (in this case 25 mg). It can be clearly seen that the dissolution of paclitaxel in PVP-K30 solid dispersion is as fast as the dissolution of paclitaxel in PVP-K17 solid dispersion. However, the amount of paclitaxel dissolved remains higher during the 4 hour test in the case of PVP-K30 solid dispersion.

The chain length of the polymeric carrier determines the crystallization time in an aqueous environment.

3.5 Effect of drug / carrier ratio

The solid dispersion used in the experiment of Example 3.5 produced after the initial experiment did not show a clear difference between the carriers. This initial experiment was performed prior to further experimentation of Example 3.4. As a result, PVP-K17 was arbitrarily selected as the carrier in other experiments.

PVP - K17  of mine Park Litexel  10% solids dispersion

Solid dispersion was prepared by dissolving 100 mg paclitaxel in 10 mL t-butanol and 900 mg PVP-K17 in 40 mL water. The paclitaxel / t-butanol solution was added to the PVP-K17 water solution with continued stirring. The final mixture was transferred to an 8 mL vial filled to a maximum volume of 2 mL. t-Butanol and water were removed by freeze-drying in succession (see Table 4).

PVP - K17  of mine Park Litexel  25% solids dispersion

Solid dispersion was prepared by dissolving 250 mg paclitaxel in 25 mL t-butanol and 750 mg PVP-K17 in 16.67 mL water. The paclitaxel / t-butanol solution was added to the PVP-K17 water solution with continued stirring. The final mixture was transferred to an 8 mL vial filled to a maximum volume of 2 mL. t-Butanol and water were removed by freeze-drying in succession (see Table 4).

PVP - K17  of mine Park Litexel  40% solids dispersion

Solid dispersion was prepared by dissolving 600 mg paclitaxel in 60 mL t-butanol and 900 mg PVP-K17 in 6.67 mL water. The paclitaxel / t-butanol solution was added to the PVP-K17 water solution with continued stirring. The final mixture was transferred to an 8 mL vial filled to a maximum volume of 2 mL. t-Butanol and water were removed by freeze-drying in succession (see Table 4).

PVP - K17  of mine Park Litexel  75% solids dispersion

Solid dispersion was prepared by dissolving 250 mg paclitaxel in 25 mL t-butanol and 83 mg PVP-K17 in 16.67 mL water. The paclitaxel / t-butanol solution was added to the PVP-K17 water solution with continued stirring. The final mixture was transferred to an 8 mL vial filled to a maximum volume of 2 mL. t-Butanol and water were removed by freeze-drying in succession (see Table 4).

Park Litexel  100% solids dispersion

Solid dispersion was prepared by dissolving 250 mg paclitaxel in 25 mL t-butanol. The paclitaxel / t-butanol solution was added to 16.67 mL water with constant stirring. The final mixture was transferred to an 8 mL vial filled to a maximum volume of 2 mL. t-Butanol and water were removed by freeze-drying in succession (see Table 4).

Dissolution test

The amount of solid dispersion powder equivalent to about 4 mg paclitaxel was placed in a 50 mL beaker. A magnetic stir bar and 25 mL water were added to the beaker. The solution was stirred at 7200 rpm. Samples were collected at multiple time points and analyzed by HPLC-UV (see Table 7).

Results and conclusions

The average results of two to three experiments are shown in FIG. The amount of dissolved paclitaxel (PCT) is expressed relative to the label claim (in this case about 4 mg). The effect of the drug / carrier is evident in Figure 9 soon. The peak concentration values of paclitaxel were inversely related to the drug / carrier ratio. The highest peak concentration reached at the lowest drug / carrier ratio (10%), while the lowest peak concentration reached at the highest drug / carrier ratio (100%). Moreover, the AUC-value of the 10% drug / carrier ratio solid dispersion was the highest, followed by the 25, 40, 75 and 100% drug / nsqkscp ratio solid dispersion.

The amount of carrier, as opposed to the amount of drug, determines the time-to-crysantrification in an aqueous environment.

3.6: Intestinal  Effect of Coating

PVP - K17  And sodium Dodecyl Welcome  Within 10% Park Litexel  40% solids dispersion

Solid dispersion was prepared by dissolving 250 mg paclitaxel in 25 mL t-butanol and 375 mg PVP-K17 and 62.5 mg sodium dodecylsulfate (SDS) in 16.67 mL water. The praklitaxel / t-butanol solution was added to the PVP-K17 / sodium dodecyl sulfite / water solution with constant stirring. The final mixture was transferred to an 8 mL vial filled to a maximum volume of 2 mL. t-Butanol and water were removed by freeze-drying in succession (see Table 4).

Park Litexel / PVP - K17 / Sodium Dodecyl Welcome  25 of solid dispersion mg Park Litexel  capsule

68.75 mg of paclitaxel 20% / PVP-K17 / sodium dodecylsulfate 10% solids dispersion (= 25 mg paclitaxel) was mixed with 160 mg lactose and 10 mg croscarmellose sodium. The resultant powder mixture was encapsulated (see Table 13).

Formulation of 25 mg paclitaxel / PVP-K17 / sodium dodecylsulfate solid dispersion capsule ingredient Amount (mg) Paclitaxel (in solid dispersion) 25 mg PVP-K17 (in solid dispersion) 37.5 mg Sodium dodecyl sulphite (in solid dispersion) 6.25 mg Lactose monohydrate 125 mg Croscarmellose sodium 10 mg

Dissolution test

The capsules were subjected to duplow in two different dissolution tests. The first test was two ordered dissolution tests, which dissolve in hypothetical gastric juice (SGF _sp ; see Table 14) without 500 mL of pepsin, followed by 629 mL of hypothetical serous fluid without pepsin (SGF _sp ; Table 14 ) For two hours. The second test was performed in a simulated intestinal fluid (FaSSIF; see Table 15) medium with 500 mL fasting for 4 hours.

Two dissolution tests were performed in a USP2 (paddle) dissolution apparatus while maintaining 37 DEG C and a paddle rotation rate of 75 rpm in a 500 mL medium. The SGF _sp mediator was changed to the SIF _sp mediator for the addition of a 129 mL switch medium. Samples were collected at multiple time points and analyzed by HPLC-UV (see Table 7).

SGF _sp , SIF _sp and switch media [96] Medium volume ingredient SGF _sp (USP 26) 500 mL 1.0 g NaCl, 3.5 mL HCl, q.s. 500 mL of water for injection Switch medium 129 mL 4.08 g KH ₂ PO 4, 30 mL NaOH solution 80 g / L (2.0 M), 129 mL water for injection SIF _sp + NaCL (USP 24) 629ML 500 mL SGF _sp And 129mL switch medium

Fasting status Virtual epidermis (FaSSIF) mediators [97] ingredient amount KH ₂ PO 4 3.9 g NaOH q.s. pH 6.5 Na taurocholate 3mM lecithin 0.75 mM KCl 7.7 g Distilled water q.s. 1L

Results and conclusions

The results are shown in FIG. The amount of dissolved paclitaxel is expressed relative to the label claim (in this case 25 mg). Fasting state The paclitaxel dissolution in simulated intestinal juice is about 20% higher than in hypothetical gastric juices. The amount of paclitaxel in solution after two hours in SGF _sp is only slightly increased when the medium is changed to simulated intestinal fluid (SIF _sp ).

The enteric coating will inhibit the release of the taxane on the top, thus inhibiting the degradation of the active ingredient. Moreover, this will allow targeted delivery to the intestine where the taksen is absorbed, so that the limited time that the taksen is present in the solution (before crystallization occurs) takes place only at the site where absorption is possible.

Example  4- Docetaxel  Oral formulation

Materials and methods

The formulations used in the following experiments were prepared according to the following outline and the compositions are depicted in Table 16.

Pure amorphous Doclex

Amorphous docetaxel was used as obtained from ScinoPharm, Taiwan.

Pure amorphous Doclex

Docetaxel was amorphized by dissolving 300 mg docetaxel anhydrous in 30 mL t-butanol. The docetaxel / t-butanol solution was added to 20 mL water (WfI) with constant stirring. The final mixture was transferred to a stainless steel lyophilization box (Gastronorm size 1/9) and t-butanol and water were removed by freeze-drying in succession (see Table 17).

Physical mixture

The physical mixture was prepared by induction and mortar mixing of 150 mg of docetaxel and a corresponding amount of carrier and surfactant (see Table 16).

Solid dispersion

Solid dispersion was obtained by dissolving 300 mg docetaxel anhydride in 30 mL t-butanol and a corresponding amount of carrier and surfactant (see Table 16) in 20 mL water for injection. The docetaxel / t-butanol solution was added to the carrier / surfactant / WfI solution with constant stirring. The final mixture was transferred to a stainless steel lyophilization box (Gastronorm size 1/9) and t-butanol and water were removed by freeze-drying in succession (see Table 17).

The composition of the tested formulation Formulation type drug part Amount (mg) Carrier part Amount (mg) Surfactants Amount (mg) part A Pure drug Anhydrous docetaxel One 150 - - - - B Pure drug Amorphous docetaxel One 450 - - - - C Physical mixture Anhydrous docetaxel 1/11 150 PVP-K30 9/11 1350 SDS 150 1/11 D Physical mixture Amorphous docetaxel 1/11 150 PVP-K30 9/11 1350 SDS 150 1/11 E Solid dispersion Amorphous docetaxel 1/11 300 PVP-K30 9/11 2700 SDS 300 1/11 F Solid dispersion Amorphous docetaxel 1/11 300 HPβ-CD ¹ 9/11 2700 SDS 300 1/11 G Solid dispersion Amorphous docetaxel 1/11 300 PVP-K12 9/11 2700 SDS 300 1/11 H Solid dispersion Amorphous docetaxel 1/11 300 PVP-K17 9/11 2700 SDS 300 1/11 I Solid dispersion Amorphous docetaxel 1/11 300 PVP-K25 9/11 2700 SDS 300 1/11 J Solid dispersion Amorphous docetaxel 1/11 300 PVP-K90 9/11 2700 SDS 300 1/11 K Solid dispersion Amorphous docetaxel 5/7 300 PVP-K30 5/21 100 SDS 20 1/21 L Solid dispersion Amorphous docetaxel 1/3 300 PVP-K30 1/2 450 SDS 150 1/6 M Solid dispersion Amorphous docetaxel 1/6 300 PVP-K30 2/3 1200 SDS 300 1/6 N Solid dispersion Amorphous docetaxel 1/21 300 PVP-K30 19/21 5700 SDS 300 1/21

¹ HP beta -CD is hydroxypropyl -? - cyclodextrin.

Freeze-drying conditions step Time (hh: mm) Storage temperature (℃) Actual pressure (mbar) Maximum pressure (mbar) One 00:00 around 1000 1000 2 01:00 -35 1000 1000 3 03:00 -35 1000 1000 4 03:01 -35 0.2 0.6 5 48:00 -35 0.2 0.6 6 63:00 25 0.2 0.6 7 66:00 25 0.2 0.6

Dissolution test

Approximately 6 mg of docetaxel and an equivalent amount of powder were placed in a 50 mL beaker. A magnetic stir bar and 25 mL water were added to the beaker. The solution was stirred at 720 rpm and maintained at about 37 占 폚. Samples were collected at multiple time points and filtered using a 0.45 mu m filter before they were diluted with a 1: 4 v / v methanol and acetonitrile mixture. The filtered and diluted samples were analyzed sequentially by HPLC-UV (see Table 18).

Chromatographic conditions column Apex octyl 150 x 4.6 mm 5 m Eluens Methanol / acetonitrile / 0.02M ammonium acetate 1/4/5 v / v / v Flow 1.0 mL / min Injection volume 10 μl Uptime 20 minutes Detection wavelength 227 nm

4.1: Type of formulation

In the first experiment, the effect of formulation type on dissolution of docetaxel was tested. Data from dissolution tests performed on Formulations A through E were compared. The results are shown in FIG. Formulation E was tested four times and Formulations A to D were tested twice.

result

Formulation A (pure docetaxel anhydride) reaches a maximum concentration of about 12 μg / mL (4.7% in total docetaxel) after 5 minutes of stirring and reaches an equilibrium concentration of about 6 μg / mL (2.2%) after 15 minutes of stirring .

Formulation B (pure amorphous docetaxel) reaches a maximum of 32 μg / mL (13%) after 0.5 minutes, and from 10 to 60 minutes the solubility is similar to that of Formulation A.

Formulation C (a physical mixture of anhydrous docetaxel, PVP-K30 and SDS) reaches a concentration of about 85 μg / mL (37%) after 5 minutes. Between 15 and 25 minutes, the docetaxel concentration rapidly decreases from 85 μg / mL (37%) to 30 μg / mL (12%) and further decreases to 20 μg / mL (9%) at 60 minutes.

Formulation D (a physical mixture of amorphous docetaxel, PVP-K30 and SDS) reaches the highest maximum concentration of 213 μg / mL (90%) after 5 minutes. Between 10 and 25 minutes, the amount of docetaxel in the solution rapidly decreases to give an equilibrium concentration of 20 μg / mL (8%) after 45 minutes.

conclusion

All formulations initially show higher solubility and decrease to equilibrium solubility after 45-60 minutes of stirring. The reduction in solubility is caused by crystallization of docetaxel as a result of supersaturated solution. The degree of super saturation depends on the physical state of the drug, ie whether it is amorphous or crystalline. When PVP-K30 is the carrier, the supersaturated state is maintained longer and the solubility of docetaxel does not rapidly decrease. Furthermore, the results show that the use of amorphous docetaxel significantly increases the solubility of docetaxel compared to anhydrous docetaxel. Furthermore, amorphous docetaxel shows a peak, which is a relatively high dissolution rate at about 5 to 7.5 minutes.

This experiment shows that the amount of docetaxel in solution is significantly increased by physical mixing of anhydrous docetaxel with PVP-K30 and SDS, and the physical mixing of amorphous docetaxel with PVP-K30 and SDS is even more so. However, the greatest increase in solubility is achieved by the introduction of docetaxel in solid dispersion of PVP-K30 and SDS.

4.2: Carrier type

In a second experiment, the effect of carrier type on the solubility of docetaxel was tested. The data in dissolution tests performed on Formulations E and F were compared. The results are shown in FIG. Formulation E was tested four times and Formulation F was tested twice.

result

Formulation E (solid dispersion of amorphous docetaxel, PVP-K30 and SDS) has the highest maximum concentration of 213 μg / mL (90% of total docetaxel present) reached after 5 minutes. Between 10 and 25 minutes, the amount of docetaxel in the solution decreased sharply and resulted in an equilibrium concentration of 20 μg / mL (8%) after 45 minutes.

Formulation F (solid dispersion of amorphous docetaxel, HPβ-CD and SDS) reaches a maximal concentration of docetaxel of about 200 μg / mL (81%) after about 2 minutes. Between 5 and 10 minutes, the amount of docetaxel in the solution drops to a value of 16 / / mL (6%) and reaches an equilibrium concentration of 11 / / mL (4%) after 45 minutes.

conclusion

This experiment shows that both PVP-K30 and HPβ-CD increase the solubility of docetaxel. Compared to HPβ-CD when PVP-K30 was used as a vehicle, the maximum docetaxel concentration was slightly higher and the supersaturation was maintained longer, so the solubility of docetaxel did not decrease rapidly over time. Furthermore, the equilibrium concentration reached after precipitation of docetaxel was higher than that of HPβ-CD in the presence of PVP-K30.

4.3: Chain length

In a third experiment, the effect of PVP chain length on the solubility of docetaxel was tested. The data of dissolution tests performed in Formulations E and G to J were compared. The results are shown in FIG. Formulation E was tested four times and Formulations G through J were tested twice.

result

Formulation G (PVP-K12) reaches a maximum concentration of docetaxel of 206 / / mL (77% of total docetaxel present) after 5 minutes. Between 5 and 30 minutes, the amount of docetaxel in the solution decreases to 20 μg / mL (7%) and the concentration of docetaxel at 45 minutes is 17 μg / mL (6%).

Formulation H (PVP-K-17) reached a maximum concentration of docetaxel of 200 μg / mL (83%) after 5 minutes and this concentration was maintained for 10 minutes with stirring, after which the amount of docetaxel in the solution was 44 μg / mL 18%) and falls to 22 / / mL (9%) about 30 minutes. The equilibrium concentration between 45 and 60 minutes is about 21 / / mL (8%).

Formulation I (PVP-K25) reaches a maximum concentration of docetaxel of 214 μg / mL (88%) after 5 minutes of stirring. The amount of docetaxel in solution is reduced to 22 μg / mL (9%) between 10 minutes and 30 minutes and a concentration of 19 μg / mL (8%) of docetaxel at 60 minutes.

Formulation E (PVP-K30) has a maximum concentration of docetaxel of 213 μg / mL (90%) reaching after 5 minutes. Between 10 and 25 minutes, the amount of docetaxel in the solution decreases sharply and yields an equilibrium concentration of 20 μg / mL (8%) after 45 minutes.

Formulation J (PVP-K90) reaches a maximum concentration of docetaxel of 214 μg / mL (88%) after 10 minutes of stirring. The amount of docetaxel in solution at 15 minutes is still 151 μg / mL (61%). After 60 min, the concentration of docetaxel is reduced to 19 μg / mL (7%).

conclusion

This experiment shows that the PVP chain length affects both the degree of super saturation and the duration of the super saturation. The use of longer PVP chain lengths results in higher maximal docetaxel concentrations and longer super saturation periods, thus higher solubility for longer periods.

4.4: Drug loading

In the fourth experiment, the effect of drug loading on the solubility of docetaxel was tested. The data of dissolution tests performed on Formulations E and K to N were compared. The results are shown in Fig. Formulation E was tested four times and formulations K to N were tested twice.

Formulation N (1/21 docetaxel per total composition weight; 5:95 w / w docetaxel vs. PVP) reaches a maximum docetaxel concentration of 197 μg / mL (79% of total docetaxel) after 10 minutes. After 15 minutes, the amount of docetaxel in the solution is still 120 μg / mL (48%) and the concentration of docetaxel decreases to 24 μg / mL (12%) between 15 minutes and 30 minutes. At 60 min the concentration of docetaxel is 20 μg / mL (8%).

Formulation E (1/11 docetaxel per total composition weight; 10:90 w / w docetaxel versus PVP) has a maximum concentration of 213 μg / mL (90%) reached after 5 minutes. Between 10 and 30 minutes, the amount of docetaxel in the solution decreases sharply and reaches an equilibrium concentration of 20 μg / mL (8%) after 45 minutes.

Formulation M (1/6 docetaxel per total composition weight; 20:80 w / w docetaxel vs. PVP) has a docetaxel concentration of 196 μg / mL (80%) after 10 minutes of stirring. The amount of docetaxel in solution is from 10 minutes to 30 (10%) between 1 minute and 60 minutes and the concentration of docetaxel is 18 μg / mL (7%).

Formulation L (1/3 of docetaxel per total composition weight; 40:60 w / w docetaxel vs. PVP) reaches a docetaxel concentration of 176 μg / mL (71%). Between 10 and 15 minutes, the amount of docetaxel in the solution drops to 46 μg / mL (18%) and after 60 minutes the amount of docetaxel in the solution is 18 μg / mL (7%).

Formulation K (5/7 docetaxel per total composition weight; 75:25 w / w docetaxel vs. PVP) reaches a maximum docetaxel value of 172 μg / mL (71%) after 5 minutes of stirring. Between 5 and 10 minutes, the docetaxel concentration sharply decreases to 42 μg / mL (17%) and after 60 minutes, the concentration of docetaxel reaches 18 μg / mL (7%).

conclusion

This experiment shows that the amount of PVP-K30 proportional to the amount of docetaxel used in solid dispersion affects the degree of super saturation and the saturation duration. The use of a higher drug load results in a lower maximum docetaxel concentration and a shorter super saturation period, thus lower solubility over time.

4.5: Solubility comparison with prior art compositions

In this experiment, a composition comprising solid dispersion of 15 mg of docetaxel, 135 mg of PVP-K30 and 15 mg of SDS was compared with literature data of a composition comprising 5 mg of docetaxel disclosed in Chen et al. [95] and a solid dispersion of PVP-K30. The solubility results were obtained using the dissolution test described in Chen et al. [95] and are shown in Figures 15 and 16. Dissolution testing was also performed on hypothetical serous fluid and compared with Chen's literature data. The results are shown in FIG.

result

From Fig. 15, it can be seen that a composition such as Chen can dissolve about 80% of the 5 mg docetaxel in the composition at up to 900 mL water. It took over 5 hours to reach this maximum. The docetaxel, PVP-K30 and SDS compositions dissolved in 100% of 15 mg docetaxel in about 60 minutes.

In Figure 16, the absolute concentration of docetaxel is given. The composition of Chen gave a maximum concentration of docetaxel of about 4.2 μg / mL after about 5 hours. The docetaxel, PVP-K30 and SDS compositions gave a maximum concentration of docetaxel of about 16.7 g / mL after about 60 minutes.

In FIG. 17, the docetaxel capsules reach a solubility of 28 μg / mL (> 90% solubility). The solid dispersion (docetaxel + PVP K30) described by Chen et al. Achieves a solubility of 4.2 g / mL (less than 80% of the 5 mg docetaxel solid dispersion tested for dissolution at 900 mL). The capsule formulation therefore achieves 6.6-fold better solubility with a higher dissolution rate (maximum reached after 30 minutes versus 90-120 minutes by Chen).

conclusion

From these results, it can be seen that the docetaxel, PVP-K30 and SDS compositions give a faster dissolution rate and higher solubility than the Chen composition. For bioavailability, it is important to see how quickly the drug dissolves and what solubility is achieved within 0.5 to 1.5 hours.

From the results of Chen, one of ordinary skill in the art will not consider that increasing the amount of docetaxel in the composition will increase the absolute solubility of docetaxel. Since Chen's composition dissolved only 80% (ie, 4 mg) of 5 mg docetaxel in 900 mL water, you would not expect that increasing the amount of docetaxel to 15 mg would result in more dissolution than 4 mg docetaxel. Therefore, you will expect that 15 mg docetaxel according to Chen will dissolve up to about 27% docetaxel relative to 100% of the docetaxel, PVP-K30 and SDS compositions. The docetaxel, PVP-K30 and SDS compositions thus provide surprisingly good results compared to Chen.

4.6: Virtual hypoallergenic plate creatine ( Simulated Intestinal Fluid sine  Pancreatin, SIF _sp ) In the dissolution test

In this experiment, dissolution of capsules containing solid dispersion of docetaxel, PVP-K30 and SDS was tested in hypothetical serous pancreatin (SIF _sp ). The capsules contained 15 mg docetaxel according to Formulation E (see Table 16). The SIF _sp was manufactured according to USP 28. Capsules containing 15 mg of docetaxel were dissolved in 500 mL of USP SIF _sp at 37 DEG C and 75 rpm with stirring. The results are shown in Figures 18 and 19.

Figures 18 and 19 show that nearly 100% of docetaxel dissolved, which is equivalent to an absolute docetaxel concentration of about 29 μg / ml and is achieved in about 30 minutes. Therefore, the composition provides relatively high solubility in a relatively short time.

4.7: Stability

The solid dispersions of docetaxel, PVP-K30 and SDS according to Formulation E (see Table 16) and those used in the capsules for clinical trials were analyzed for chemical (no degradation) and physical (No change in dissolution characteristics).

Example  5: Clinical trial data according to formulation

Materials and methods

Ten patients participated in the ongoing clinical trial Ⅰ

These patients were given the following numbers.

301, 302, 303, 304, 305, 306, 307, 308, 309 and 310.

These patients were given a liquid formulation of docetaxel or a formulation consisting of a solid composition comprising solid dispersion of docetaxel, PVP-K30 and SDS (hereinafter referred to as MODRA).

Liquid formulation

Doses of docetaxel: 30 mg for all patients (except for patient 306 who received 20 mg docetaxel). The 30 mg dose was prepared as follows: 3.0 mL Taxotere® 10 mg docetaxel per ml in a premix for intravenous administration (polysorbate 80 (25% v / v), ethanol (10% ) Was mixed with water to a final volume of 25 mL. This solution was taken orally by the patient with 100 mL tap water.

MODRA

Dose of docetaxel 30 mg; Two capsules were taken with 15 mg docetaxel per capsule. Formulations E (1/11 docetaxel, 9/11 PVP-K30 and 1/11 SDS) from the previous example were selected for the additional testing of clinical studies. A new batch of formulation E was prepared by dissolving 1200 mg anhydrous docetaxel in 120 mL t-butanol and 10800 mg PVP-K30 and 1200 mg SDS (see Table 16) in 80 mL water for injection. The docetaxel / t-butanol solution was added to the PVP-K30 / SDS / WfI solution with continued stirring. The final mixture was transferred to a stainless steel lyophilization box (Gastronorm size 1/3), and t-butanol and water were sequentially removed by lyophilization (see Table 17).

A total of 60 gelatin capsules of size 0 were filled with an amount of solid dispersion equivalent to 15 mg docetaxel and HLPC analysis was used to determine the correct amount of docetaxel per mg of solid dispersion. The assay confirmed that the capsules contained 15 mg docetaxel.

The patient was prescribed orally with 100 mL tap water on the morning fasting.

Patient treatment

Patients 301, 302, 303, 304 and 305 received only liquid formulations.

Patient 306 received 20 mg docetaxel + ritonavir as a liquid formulation in the first cycle, plus additional ritonavir 4 hours after dosing with docetaxel plus the same prescription in the second cycle.

Patients 307, 308, 309 and 310 received liquid formulations and / or MODRA. Cycles were administered at intervals of one week.

According to institutional guidelines, all patients were treated with oral dexamethasone for both oral and intravenous docetaxel. A dose of 4 mg of dexamethasone was given 1 hour before the test drug, followed by 4 mg every 12 hours (2 times). Docetaxel therapy hour ago, patients also received 1mg that Rani set theory (key Trillium ^®) for the prevention of nausea and vomiting.

After drug administration, blood samples were collected for pharmacokinetic analysis. Bone samples were taken prior to dosing. Blood samples were centrifuged and the plasma separated and stored immediately at -20 ° C until analysis. The assay was performed in a GLP (Good Laboratory Standards) certified laboratory approved HPLC method [101].

result

Table 19 provides an overview of each pharmacokinetic outcome.

ID cure cycle Tlast (h) Concentration last AUClast AUCinf 306 20 mg docLF 1 x RTV One 48.03 0,668 242,7 256,5 306 20 mg docLF 2 x RTV 2 48,02 1,34 357,2 384,5 301 30mg docLF 2 47,78 1,42 556,7 586.5 302 30mg docLF 2 8.15 141 2227,1 3028,1 303 30mg docLF 2 48 3.28 663,9 745,4 304 30mg docLF 2 47,77 2.67 723,4 761,3 305 30mg docLF 2 48.07 0,498 129,8 140,5 307 30mg docLF 3 23,9 5,17 754,3 822,0 309 30mg docLF One 24,02 14,1 2127,5 2327,0 310 30mg docLF One 24,17 6.17 758,7 836,1 307 MODRA 30mg One 24.07 4.23 420,8 473,8 307 MODRA 30mg 2 23.97 7.05 782,1 873,6 308 MODRA 30mg One 23.95 10,9 645,7 879,2 308 MODRA 30mg 2 24,02 7.76 507,3 625,9 309 MODRA 30mg 2 23,8 7.09 892,2 994,1 310 MODRA 30mg 2 23,63 8.52 650,7 760,3

docLF: docetaxel liquid formulation

MODRA: Dosetaxel capsule formulation

Tlast: Time at which the docetaxel concentration of the last sample for measurement was measured (h)

Concentration last: Concentration of docetaxel in Tlast (ng / mL)

AUClast: calculated AUC to concentration end (ng.h / mL)

AUCinf: extrapolated to AUClast + infinity (ng.h / mL)

The dose of ritonavir is 100 mg in all cases (capsule, Norvir ^® )

Patients 301, 302, 303, 304, 305, 307, 309 and 310 received liquid formulations. The 95% confidence interval for the mean and AUC averages (extrapolation to infinity) is: 1156 (+ - 348) ng * h / mL. The inter-individual variability is 85%.

Patient 306 received 20 mg docetaxel (in liquid formulation) with 100 mg ritonavir in the first cycle and the same combination in the second cycle after one week, or 100 mg additional ritonavir 4 hours after dosing docetaxel. One at t = 0 and the second at t = 4h, taking two doses of ritonavir. The pharmacokinetic curve is depicted in FIG.

Patients 307, 308, 309 and 310 received liquid formulations and / or MODRA. The pharmacokinetic curve is depicted in FIG.

Figure 22 depicts the pharmacokinetic curves of all courses (n = 6) of patients receiving liquid formulations 307, 309 and 310 and four patients receiving MODRA (307, 308, 309 and 310).

The pharmacokinetic results of MODRA versus a liquid formulation combined with both 100 mg ritonavir are summarized below:

Liquid formulation (30 mg Doclex )

AUC _inf (95% confidence interval of mean): 1156 (808-1507) ng * h / ml

Individual internal variability: 85% (n = 8)

MODRA (30 mg Doclex )

AUC _inf (95% confidence interval of mean): 768 (568-968) ng * h / ml

Individual internal variability: 29% (n = 4)

Intra-individual variability: 33% (n = 2)

The mean AUC of MODRA was calculated using six curves from four patients. The first dose of MODRA administered to each patient was used to calculate individual internal variability. The individual peripheral variability is based on data from patients 307 and 308 who received two doses of MODRA.

conclusion

The docetaxel liquid formulations tested result in an AUC value about 1.5 times higher than the same dose (30 mg) given in the new capsule formulation (MODRA).

The individual internal variability of liquid formulations is high (85%) while the individual internal variability of capsule formulations is significantly lower (29%). This is an important feature of the new capsule formulation and provides a much better predictable dose of docetaxel. Also, for reasons of safety, low individual internal variability is even more desirable in oral chemotherapy.

Individual peripheral variability (limited data) is of the same magnitude as individual internal variability.

The second additional dose of 100 mg ritonavir taken 4 hours after docetaxel administration increases the docetaxel AUC 1.5-fold.

Comparison of Oral Capsule Formulations versus Intravenous Administration

Figure 23 shows the results of pharmacokinetics (n = 5) patients treated with intravenous (20 mg docetaxel, Taxotere ^® ) (n = 5 patients for 1 hour intravenous injection) and oral administration of docetaxel (30 mg docetaxel; MODRA capsules, see above) Show the enemy curve. Both intravenous and oral docetaxel were combined with administration of 100 mg ritonavir (capsule, Norvir ^® ). According to the institutional guidelines, all patients were treated with oral dexamethasone for both oral and intravenous docetaxel administration. 4 mg of dexamethasone was given 4 mg (2 times) every 1 hour before and 1 every 12 hours thereafter. 1 hour ago docetaxel therapy, patients also received 1mg that Rani set theory (key Trillium ^®) for the prevention of nausea and vomiting.

The bioavailability of the MODRA capsules was calculated by:

(AUC 30 mg oral / AUC 20 mg vein) x (20/30) x 100% = 73% (SD 18%)

This shows that bioavailability of capsules is relatively high and has low individual internal variability.

The foregoing embodiments are intended to illustrate the specific embodiments of the invention and are not intended to limit the scope thereof, which is defined by the appended claims. All documents mentioned herein are incorporated by reference in their entirety.

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Claims (78)

In the composition, the composition comprises an amorphous taxane, a hydrophilic polymeric carrier and a surfactant,
The taxane, carrier and surfactant are in solid dispersion form,
Wherein the weight ratio of the pellet to the carrier is from 2.5: 97.5 w / w to 1: 9 w / w. The method according to claim 1,
Wherein the amorphous taxanes are prepared by solvent evaporation or lyophilisation. The method according to claim 1,
Wherein the taxane is selected from the group consisting of decetaxel, paclitaxel, BMS-275183 (BMS-275183) and pharmaceutically acceptable salts thereof. The method of claim 3,
Wherein the taxane is selected from the group consisting of docetaxel, paclitaxel, and a pharmaceutically acceptable salt thereof. The method according to claim 1,
Wherein the taxane is docetaxel. The method according to claim 1,
The carrier may be selected from the group consisting of polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyvinyl alcohol (PVA), crospovidone (PVP-CL), polyvinylpyrrolidone-polyvinyl acetate copolymer -PVA), methylcellulose, hydroxypropylcellulose, carboxymethylethylcellulose, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyacrylates, polymethacrylates, sugars, polyols, and mannitol, And polymers thereof such as sucrose, sorbitol, dextrose and chitosan, and cyclodextrins. The method according to claim 1,
Wherein the carrier is PVP. 8. The method of claim 7,
Wherein the PVP is selected from the group consisting of PVP-K12, PVP-K15, PVP-K17, PVP-K25, PVP-K30, PVP-K60 and PVP-K90. 9. The method of claim 8,
Wherein the PVP is selected from the group consisting of PVP-K30, PVP-K60 and PVP-K90. The method according to claim 1,
The surfactant may be selected from the group consisting of sodium dodecylsulfate (SDS), sorbitan ester (sorbitan fatty acid ester), polyoxyethylene stearate, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil derivative, polyoxyethylene alkyl ether , Poloxamer, glyceryl monooleate, docusate sodium, cetrimide, benzyl benzoate, benzalkonium chloride, benzethonium chloride, hypromellose, An ionic emulsifying wax, an anionic emulsifying wax and triethyl citrate. &Lt; Desc / Clms Page number 13 &gt; 11. The method of claim 10,
Wherein the surfactant is SDS. The method according to claim 1,
Wherein the weight ratio of the pellet to the carrier is from 5:95 w / w to 1: 9 w / w. The method according to claim 1,
Wherein the weight ratio of the pellet to the carrier is 1: 9 w / w. The method according to claim 1,
Wherein the amorphous taxane is prepared by lyophilisation. 15. The method of claim 14,
Wherein the amorphous taxane is prepared by lyophilization of a taxane solution in capsules for oral administration. The method according to claim 1,
Lt; RTI ID = 0.0 &gt; ritonavir &lt; / RTI &gt; as an additional pharmaceutically active ingredient. delete delete 17. The method according to any one of claims 1 to 16,
Wherein the composition is a therapeutic composition. 17. The method according to any one of claims 1 to 16,
Wherein said composition is for the treatment of neoplastic disease. In the method for producing a composition,
Dissolving a tackle, a hydrophilic polymeric carrier and a surfactant in a solvent, wherein the weight ratio of the pellet to the carrier is from 2.5: 97.5 w / w to 1: 9 w / w; And
The method of any one of claims 1 to 16, comprising the step of forming the composition by lyophilization or solvent evaporation of the solution. delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete

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